Radiotherapy Treatment Assessment using DCE-MRI

Abstract

The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information.

This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.

I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising.

Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI.

II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response.

The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment.

In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.

Problematizing practice: MacIntyre and management

Alasdair MacIntyre’s distinction between institutions and practices helps illuminate how powerful institutional forces frame and constrain the practice of organizational research as well as the output and positioning of scholarly journals like Organization. Yet his conceptual frame is limited, not least because it is unclear whether the activity of managing is, or is not, a practice. This article builds on MacIntyre’s ideas by incorporating Aristotle’s concepts of poíēsis, praxis, téchnē and phrónēsis. Rather than ask, following MacIntyre, whether management is a practice, this wider network of concepts provides a richer frame for understanding the nature of managing and the appropriate role for academia. The article outlines a phronetic paradigm for organizational inquiry, and concludes by briefly examining the implications of such a paradigm for research and learning.

Sensemaking, safety, and situated communities in (con)temporary networks

This paper discusses the difficulties involved in managing knowledge-intensive, multinational, multiorganisational, and multifunctional project networks. The study is based on a 2-year quasi-ethnography of one such network engaged in the design and development of a complex new process control system for an existing pharmaceutical plant in Ireland. The case describes how, drawing upon the organisational heritage of the corporations involved and the logic implicit within their global partnership arrangements, the project was initially structured in an aspatial manner that underestimated the complexity of the development process and the social relations required to support it. Following dissatisfaction with initial progress, a number of critical management interventions were made, which appeared to contribute to a recasting of the network ontology that facilitated the cultivation and protection of more appropriate communicative spaces. The case emphasises the need to move away from rationalistic assumptions about communication processes within projects of this nature, towards a richer conceptualisation of such enterprises as involving collective sensemaking activities within and between situated ‘communities’ of actors. Contrary to much contemporary writing, the paper argues that space and location are of crucial importance to our understanding of network forms of organising.

Beyond MacIntyre: grounding the business as practice debate

Alasdair MacIntyre’s distinction between institutions and practices helps illuminate how powerful institutional forces frame and constrain the practice of organizational research as well as the output and positioning of scholarly journals. Yet his conceptual frame is limited, not least because it is unclear whether the activity of managing is, or is not, a practice. This paper builds on MacIntyre’s ideas by incorporating Aristotle’s concepts of poíēsis, praxis, téchnē and phrónēsis. Rather than ask, following MacIntyre, whether management is a practice, this wider network of concepts provides a richer frame for understanding the nature of managing and the appropriate role for academia. The paper outlines a phronetic paradigm for organizational inquiry, and concludes by briefly examining the implications of such a paradigm for research and learning.

HomeBank: An Online Repository of Daylong Child-Centered Audio Recordings.

HomeBank is introduced here. It is a public, permanent, extensible, online database of daylong audio recorded in naturalistic environments. HomeBank serves two primary purposes. First, it is a repository for raw audio and associated files: one database requires special permissions, and another redacted database allows unrestricted public access. Associated files include metadata such as participant demographics and clinical diagnostics, automated annotations, and human-generated transcriptions and annotations. Many recordings use the child-perspective LENA recorders (LENA Research Foundation, Boulder, Colorado, United States), but various recordings and metadata can be accommodated. The HomeBank database can have both vetted and unvetted recordings, with different levels of accessibility. Additionally, HomeBank is an open repository for processing and analysis tools for HomeBank or similar data sets. HomeBank is flexible for users and contributors, making primary data available to researchers, especially those in child development, linguistics, and audio engineering. HomeBank facilitates researchers' access to large-scale data and tools, linking the acoustic, auditory, and linguistic characteristics of children's environments with a variety of variables including socioeconomic status, family characteristics, language trajectories, and disorders. Automated processing applied to daylong home audio recordings is now becoming widely used in early intervention initiatives, helping parents to provide richer speech input to at-risk children.

The Didache and Traditioned Innovation: Shaping Christian Community in the First Century and the Twenty-First Century

Church leaders, both lay and clergy, shape Christian community. Among their central tasks are: building communal identity, nurturing Christian practices, and developing faithful structures. When it comes to understanding the approach of the earliest Christian communities to these tasks, the Didache might well be the most important text most twenty-first century church leaders have never read. The Didache innovated on tradition, shaping the second generation of Christians to meet the crises and challenges of a changing world.

Most likely composed in the second half of the first century, the Didache served as a training manual for gentile converts to Christianity, preparing them for life in Christian community. This brief document, roughly one third the length of Mark’s gospel, developed within early Jewish-Christian communities. It soon found wide usage throughout the Mediterranean region, and its influence endured throughout the patristic and into the medieval period.

The Didache outlines emerging Christian practices that were rooted in both Jewish tradition and early Jesus material, yet were reaching forward in innovative ways. The Didache adopts historical teachings and practices and then adapts them for an evolving context. In this respect, the writers of the Didache, as well as the community shaped by its message, exemplify the pattern of thinking described by Greg Jones as “traditioned innovation.”

The Didache invites reflection on the shape and content of Christian community and Christian leadership in the twenty-first century. As churches and church leaders engage a rapidly changing world, the Didache is an unlikely and yet important conversation partner from two millennia ago. A quick read through its pages – a task accomplished in less than half an hour – brings the reader face to face with a brand of Christianity both very familiar and strikingly dissimilar to modern Christianity. Such dissonance challenges current assumptions about the church and creates a space in which to re-imagine our situation in light of this ancient Christian tradition. The Didache provides a window through which we might re-examine current conceptualizations of Christian life, liturgy, and leadership.

This thesis begins with an exploration of the form and function of the Didache and an examination of a number of important background issues for the informed study of the Didache. The central chapters of this thesis exegete and explore select passages in each of the three primary sections of the Didache – the Two Ways (Didache 1-6), the liturgical section (Didache 7-10), and the church order (Didache 11-15). In each instance, the composers of the Didache reach back into a cherished and life-giving aspect of the community’s heritage and shape it anew into a fresh and faithful approach to living the Christian life in a drastically different context.

The thesis concludes with three suggestions of how the Didache may provide a resource for the way the Church in the present thinks about training disciples, shaping community, and developing leadership structures. These conversation starters offer beginning points for a richer, fuller discussion of traditioned innovation in our current church context. The Didache provides a source of wisdom from our spiritual forebears that modern Christian leaders would do well not to ignore. With a look through the first century window of the Didache, twenty-first century Christians can discover fresh insights for shaping Christian community in the present.

Ireland and the global economic crisis: one island, two different experiences

In this chapter, Ó hAdhmaill argues that responses to the global economic crisis which emerged in 2008 reflected a dominant ideological discourse, with ‘austerity’ being a tool in a wider agenda to reassert neoliberalist thinking in the global economy and welfare provision in the richer countries. In Ireland, North and South, however, the experience of, and responses to, the crisis and ‘austerity’ were different, reflecting different social, economic, and political contexts and influences, as well as different levels of democratic control. Ó hAdhmaill outlines some of these differences and argues that, while democratic control in smaller jurisdictions may be limited by the ‘real rulers’ of the world, global capital, people still have ‘agency’ and do not have to be mere passive observers of unfolding events.

Un lieu balzacien : le boudoir : topocritique de la Comédie humaine d'Honoré de Balzac

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Remodelage de la chromatine lors de l'activation transcriptionnelle synergique de cdx1 par l'acide rétinoïque et par Wnt3a

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Bases neurologiques du phénomène de masquage visuel

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

(Appendix) Total organic carbon, pyrolysis characteristics, and organic matter types at DSDP Holes 77-535 and 77-540

Lower to middle Cretaceous sediments in the eastern Gulf of Mexico are richer in organic matter and have a more marine organic facies than their counterparts in the nearby western North Atlantic, suggesting that the Gulf was the more productive of the two areas. As in the western North Atlantic, the rate of supply of terrestrial organic matter was high when the rate of supply of noncarbonate clastic materials was high (at times of low sea level) and diminished as sea level rose. The rate of supply of marine organic matter was lower in the Early Cretaceous than in the Cenomanian, perhaps in response to the global rise in sea level over this period. Where they are thermally mature, the organic matterrich units drilled at Sites 535 and 540 should be excellent sources for liquid hydrocarbons. The Pleistocene sediments of the eastern Gulf are dominated by terrestrial organic matter representing Mississippi River effluent.

Descriptions of 104 gravity and piston sediment cores from POLARSTERN expedition ARK-VIII/3 to the Arctic Ocean

Sediment descriptions and lithostratigraphy (chapter 6.4) NANSEN BASIN The upperrnost 20-50 cm of sedirnents in the Nansen Basin norrnally cornprise soft dark brown, brown-grayish and brown clay. Except for the toprnost clay, the four piston cores retrieved, contained quite different lithologies: a rnuddy diarnicton with outsized clasts (PS2157-6), sandy-silt beds alternating with clay beds (PS2159-6), and silty clay beds of brownish and grayish colours (PS2161-3). Core PS2208-3 was retrieved frorn a plateau on a searnount. The plateau was serni-encircled by hills. The upper 250 cm of this core cornprise brown and olive brown clays. Below these are several sandlayers and a 74 cm thick unit of a sandy mud with rnud-clasts up to 20 cm in diameter. GAKKEL RIDGE The uppermost 20-50 cm of sediments on the Gakkel Ridge comprise soft dark brown, brown, grayish brown clay. In most of the cores there are two horizons of brown clay separated by olive brown clay. The upper horizon is darker. The older stratigraphy is rather varied. Core PS2165-1 contains several thin gray sandlsilt layers, probably distal turbidites. The sarne is found in Core PS2167-1. This core also has a thick (approx. 2 rn) coarse grained turbidite containing large rnud clasts and basaltic rock fragrnents. The color of the turbiditic layers is dark gray. There are several horizons of hernipelagic sandylsilty clays with quite a variety in colours; black, gray, olive, brown, yellowish brown and reddish. The colour variation rnay be due to hydrotherrnal activity or provenance or a shift in redox potential. Cores PS2168-2 and PS2169-1 have typical sequences of very dark gray sandy mud with sharp lower boundaries grading upwards into olive brown clay. Below the lower boundary is often a thin (1-2 cm) gray clay layer. AMUNDSEN BASIN The giant box cores (GKG) provided in most cases excellently preserved sedirnent surfaces which consisted in the entire Amundsen Basin of dark brown to dark grayish brown silty clay with few dropstones and common calcareous microfossils (foraminifers and calcareous nannofossils). The brown and grayish brown color of the sediment surface is a result of the oxidizing conditions at the seafloor due to the rapid renewal of the bottom water rnasses. Planktic forarninifers and calcareous nannofossils are relatively frequent and well preserved despite the rernote location of the basin and its water depths of >4000 rn. Srnear slide descriptions have shown that the surface sedirnents consist dorninantly of clays to silty rnuds with clay rninerals and quartz as the rnost important constituents. The coarse fractions contained besides planktic and benthic forarninifers and coarse clastic rnaterials, rare bivalves, dropstones and mud clasts. The Station PS2190 at the North Pole is a particular good exarnple of the type of sedirnents deposited at the sea floor surface of the Arnundsen Basin, with hornogenous dark brown soft clay covering a sedirnent sequence of highly variable cornposition. Nurnerous giant box cores also provide insight into the detailed lithostratigraphy of the upperrnost sedirnent layers. Twelve box cores have been collected frorn the Arnundsen Basin. Below the youngest unit of 5-20 crn thick silty clays deposits of variable stratigraphies have been found, rnostly consisting of clays or silty clays. In a few instances turbidites have been observed. Benthic forarninifers have not been found in the surface sedirnents. Other fossils were extrernely rare. Bioturbation is weakly developed on all stations. Benthic anirnals seern to live only in and on the upperrnost 2 cm of the uppermost sediment layer. They cornprise amphipods (on all stations) and holothurians, bryozoans, polychaetes, and porifers at one station each. LOMONOSOV RIDGE Sediments from the Lomonosov Ridge show a variety of colors and textures. Following smear slide analyses they are composed mostly of clay minerals and quartz with mica and feldspars, especially in the siltier and sandier parts. Volcanic glass, microcrystalline carbonate, opaque minerals and green amphibole are occasional accessories. The sediments from the Lomonosov Ridge show a noticeable difference from sediments collected from the surrounding basins. Lomonosov Ridge sediments are richer in silt and sand than basin sediments. Occasional turbidites occur in ridge sediments but these must be of entirely local origin. The ridge sediments include frequent layers of "cottage cheese" texture made up of what appear to be small, angular mud clasts of a variety of colors.

Sedimentology of core M74/4_1143-1

Periplatform ooze is an admixture of pelagic carbonate and sediment derived from neritic carbonate platforms. Compositional variations of periplatform ooze allow the rectonstruction of past sea-level changes. Periplatform ooze formed during sea-level highstands is finer grained and richer in aragonit through the elevated input of material from the flooded platform compared to periplatform ooze formed during the episodes of lowered sea level. In many cases, however, the sea floor around carbonate platforms is subjected to bottom currents which are expected to affect sediment composition, i.e. through winnowing of the fine fraction. The interaction of sea-level driven highstand shedding and current impact on the formation of periplatform ooze is influenced or even distorted by changing current activity, an integrated study using seismic, hydroacoustic and sedimentological data has been performed on periplatform ooze deposited in the Inner Sea of the Maldives. The Miocene to Pleistocene succession of drift deposits is subdivided into nine units; limits of seismostratigraphic units correspond to changes or turnarounds in grain size trends in cores recovered at ODP Site 716 and NEOMA Site 1143. For the Pleistocene it can be shown how changes in grain size occur in concert with sea-level changes and changes of the monsoonal system, which is thought to be a major driver bottom currents in the Maldives. A clear hightstand shedding pattern only appears in the data at a time of of relaxation of monsoonal strength during the last 315 ky. Results imply (1) that drift sediments provide a potential target for analyzing past changes in oceanic currents and (2) that the ooze composition bears a mixed signal of input and physical winnowing at the sea floor.

The seasonal sea-ice zone in the glacial Southern Ocean as a carbon sink, supplementary datasets

Reduced surface-deep ocean exchange and enhanced nutrient consumption by phytoplankton in the Southern Ocean have been linked to lower glacial atmospheric CO2. However, identification of the biological and physical conditions involved and the related processes remains incomplete. Here we specify Southern Ocean surface-subsurface contrasts using a new tool, the combined oxygen and silicon isotope measurement of diatom and radiolarian opal, in combination with numerical simulations. Our data do not indicate a permanent glacial halocline related to melt water from icebergs. Corroborated by numerical simulations, we find that glacial surface stratification was variable and linked to seasonal sea-ice changes. During glacial spring-summer, the mixed layer was relatively shallow, while deeper mixing occurred during fall-winter, allowing for surface-ocean refueling with nutrients from the deep reservoir, which was potentially richer in nutrients than today. This generated specific carbon and opal export regimes turning the glacial seasonal sea-ice zone into a carbon sink.

Elemental composition of various manganese nodules

Manganese nodules have been observed over wide areas of both the Pacific and Atlantic Oceans, however, deposits in the Pacific Ocean are generally much richer in elements of economic interest such as nickel, copper and cobalt. In understanding the genesis and the geochemistry involved in their formation and growth, it is important to know the total chemical composition of these nodules and how they vary within a given deposit and between deposits in the oceans of the world. The concentrations of elements: nickel, copper, cobalt, iron, manganese, silicon, and calcium, in all of the manganese nodules which have been analyzed were recently summarized by Horn et al. (1972). These observations indicate certain correlations, both positive and negative, between Mn and the associated elements within the nodules. Their data suggest similarities in chemical composition for nodules from a given area; however, the analyses of Mn nodules, like that of the ocean water, itself, has large errors associated with some of the measurements. This is understandable, since many of these measurements were intended to provide an approximate indication of elemental content. Where one is interested in carefully preparing a description of Mn nodule chemical composition which can serve as a basis for formulating theories regarding their genesis and subsequent geochemical changes in the ocean environment, then very precise and accurate analyses are essential. The purpose of this study has been to measure the concentrations of 18 elements in Mn nodules with a high degree of accuracy and determine what correlations exist between element concentrations. The scope of this study was seriously limited and therefore was confined to one area of the Pacific Ocean at approximately 22 N latitude, 114 W longitude, at an ocean depth of approximately 11,000 feet.