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Physics in Medicine & Biology

60th anniversary collection 2016

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Physics in Medicine & Biology 60th anniversary collection 2016

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Welcome to the 60th anniversary collection from Physics in Medicine & Biology (PMB)! We are delighted to offer this collection of papers, which showcases just a very few of the major developments that have been published in the journal since its inception in 1956.

The disciplines of physics and engineering have had an enormous impact on medical practice over the past 60 years, revolutionizing the way that patients are diagnosed and treated. In 1956, planar X-ray imaging was the primary radiographic technique available, with ultrasound and gamma-ray imaging both in their infancy. Radiation treatments using radioactive iodine were already quite common, and the first linear accelerators were being developed for external-beam radiation therapy. But the techniques available to image radiation for diagnostic purposes or deliver radiation for therapeutic purposes were still extremely crude. Ideas and developments were not only limited by hardware constraints around radiation sources, detectors and electronics, but also by the lack of computational power.

The 1960s and 1970s witnessed a revolution in the field that is still being played out to this day. The advent of tomography allowed the first cross-sectional images to be produced, leading to the rapid development and adoption of X-ray computed tomography (CT) in medical practice. The development of CT in the early 1970s and its ability to visualize the internal structures of the body non-invasively is often lauded as one of the most impactful advances ever made in medicine. The methods of tomographic reconstruction derived initially for CT also supported the development of functional and molecular tomographic imaging of radiotracers with single photon emission computed tomography (SPECT) and positron emission tomography (PET). The real-time imaging capabilities of ultrasound, which allowed the developing foetus to be safely imaged, forever changed the field of obstetrics – improving outcomes for so many mothers and their babies.

Later in that decade, the concept of frequency encoding enabled nuclear magnetic resonance signals to be turned into images with unprecedented soft-tissue contrast and gave birth to the field of magnetic resonance imaging (MRI). The advances in radiation therapy were no less dramatic. The development of compact linear accelerators that could be installed in hospitals, adjustable collimation, and more powerful computing resources that allowed radiation delivery to be carefully planned (based on advances in imaging that defined the geometry of a tumour and surrounding tissues in three dimensions) resulted in far more precise delivery of radiation to tumours. This in turn fundamentally cemented radiation therapy as one of the three primary methods for treating cancer.

The subsequent decades have seen incredible improvements in all of these diagnostic and therapeutic modalities. Advances have been fuelled by new materials, radiation sources, digital sensors, fast and high-density electronics, and sophisticated computational tools for modelling radiation interactions in matter, which are used to plan the delivery of radiation in

Welcome to Physics in Medicine & Biology

60th anniversary collection 2016

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therapy and model the detection of radiation in imaging. Other major developments included the introduction of multimodal imaging systems that exploit the synergy between different imaging techniques, and the convergence of the radiation therapy and medical imaging fields through image-guided therapy.

We now have incredibly sophisticated tools for detecting disease within the human body and for precisely delivering radiation to tumours while sparing surrounding normal tissue. Machines that can deliver protons and precisely tailor radiation dose for treating tumours near sensitive structures are becoming increasingly available in major medical centres. Imaging also has become a critical tool in surgical planning and monitoring response to a broad range of treatments. The disciplines of biomedical imaging and radiation therapy have become increasingly more quantitative, supported by the power of modern computing platforms that allow massive amounts of data to be handled, manipulated and displayed.

These advances and many more are documented in the thousands of papers that have appeared in PMB over the past 60 years. In this special collection, we have selected just a few examples from the journal that the Editorial Board and International Advisory Board felt have had a particularly important impact on the development of the field. In each case, we have asked the authors (or in cases where the authors were not available, an expert in the field) to explain the significance of the work.

It is a considerable task to even try to predict what will happen in the next 60 years. Will we see the emergence of completely new diagnostic or therapeutic modalities? How will the convergence of radiation therapy and imaging play out? How will physics and engineering impact emerging areas such as nanomedicine and precision medicine? Time will tell. For now, we hope you enjoy browsing this collection of papers and we would like to thank all of the authors, reviewers and readers of the journal for all that they have done over 60 years to make PMB the leading international journal in the field of biomedical physics and engineering.

Simon R Cherry, University of California, Davis, USAEditor-in-Chief, Physics in Medicine & Biology


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About the Institute of Physics and Engineering in Medicine

The Institute of Physics and Engineering in Medicine (IPEM) is the UK Learned Society and professional organisation for physicists, clinical and biomedical engineers and technologists working in medicine and biology. Our aim is to advance physics and engineering applied to medicine and biology for the public good, and to advance public education in the field. We do this through professional, educational and standards-focused activity; and also through a programme of public lecture and outreach activities, and increasingly by involving the public in IPEM’s work.

Originating as the Hospital Physicists’ Association in the UK in 1943, the organization became IPEM in 1997. It is a registered charity and company limited by guarantee, with a broad membership of well over 4000 physicists, clinical engineers, bioengineers and technologists. They work in hospitals, industry and universities, applying physics and engineering to medicine and biology. The fact that our members span the continuum between the generation of ideas, innovation and research in the academic world, the development and manufacture of equipment to translate that new knowledge into practice in industry, and the daily provision of safe investigation and treatment of individual patients in health services, is a unique feature of IPEM as a professional body.

IPEM is an internationally active body, being the national member organization for the UK in the International Organisation for Medical Physics (IOMP) and the European Federation of Organisations for Medical Physics (EFOMP). We are also involved with the International Federation for Medical and Biological Engineering (IFMBE), the bioengineering international counterpart of IOMP.

Our international journals are a major part of our global presence, as well as being greatly valued by our members. We are immensely proud of our titles, Physics in Medicine & Biology, Physiological Measurement, and Medical Engineering & Physics. We are very grateful for the leadership and expertise of their editors, and the hard work of the Editorial Boards, which is essential to the success of these journals.

Looking forward, IPEM’s membership is both growing and diversifying. The number of academic members of IPEM is growing with the integration of the Bioengineering Society that was announced in 2015, and these members’ activities and interests are supported by new Special Interest Groups. We have an active Industrial Advisory Group and new initiatives drawing in students at both undergraduate- and post-graduate level. Innovation and encouragement for early career members are key themes being discussed as we develop a new strategy for the future. It goes without saying that the continued success of our flagship journals in encouraging and disseminating the highest quality research in our specialist fields will always form part of our future strategy.

IPEM’s Board of Trustees would like to congratulate Physics in Medicine & Biology on its 60th anniversary and its success in attaining such a pre-eminent position in its field. We look forward to the continued success of the journal in years to come.


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PMB publishes research on all areas of radiotherapy physics and biomedical imaging.

Topics covered are:

• All areas of radiotherapy physics

• Radiation dosimetry (ionizing and non-ionizing radiation)

• Biomedical imaging (e.g. X-ray, MR, ultrasound, optical, nuclear medicine)

• Image reconstruction and kinetic modelling

• Image analysis and computer-aided detection

• Applications of nanoparticles in imaging and therapy

• Therapies (including non-ionizing radiation)

• Biomedical optics

• Radiation protection

• Radiobiology

Papers on physics with no obvious medical or biological applications, or papers that are almost entirely clinical or biological in their approach are not acceptable.

Physics in Medicine & Biology

ISSN 0031-9155

iopscience.org/pmb

The international journal of biomedical physics published by IOP Publishing on behalf of the Institute of Physics and Engineering in Medicine

Volume 61 Number 4 21 February 2016

Scope

Jon Ruffle Publisher

Sarah Obertelli Publishing Assistant

Andrew Malloy Editor

Gemma Greig Production Editor

Florence Gregson Associate Editor

Anastasia Ireland Senior Marketing Executive

Richard Kelsall Associate Editor

Tami Freeman Editor, medicalphysicsweb

Meet the PMB team

Cover image: the front cover artwork is inspired by specialist imagery of PET scans. The graphical shapes found in technical graphs and diagrams such as PET detector arrays have served to feed into this artistic interpretation, while a blueprint version has been designed for the inside front and back cover.


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Former Editors

Throughout its history, the journal has been headed by eminent scientists. We thank them for their contribution to the development of Physics in Medicine & Biology into a world-leading publication.

Editor 1956–1961 Professor John Eric Roberts Middlesex Hospital, London

Editor 1983–1985 Professor Roy P Parker University of Leeds, Leeds

Editor 1996–1999 Professor Martin O Leach Royal Marsden NHS Foundation Trust, London

Editor 1973–1978 Professor Harold A B Simons Royal Free Hospital, London

Editor 1988–1991 Professor Stephen C Lillicrap Royal United Hospital, Bath

Editor 2006–2011 Professor Steve Webb Royal Marsden NHS Foundation Trust, London

Editor 1961–1972 Professor Sir Joseph Rotblat

St Bartholomew’s Hospital, London

Editor 1986–1987 Dr Michael J Day

Newcastle General Hospital, Newcastle

Editor 2000–2005 Professor Alun H Beddoe

University Hospital, Birmingham

Editor 1979–1982 Professor John Clifton

University College Hospital, London

Editor 1992–1995 Professor Brian L Diffey

Dryburn Hospital, Durham

Editor 2012–present Professor Simon Cherry

University of California, Davis, USA


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Editorial Board

International Advisory Board

Editor-in-Chief Deputy Editor

M S Alber Aarhus University, DenmarkO Baffa University of Sao Paulo, BrazilP Beard University College London, UKA H Beddoe Queen Elizabeth Hospital, Birmingham, UKF J Beekman Delft University of Technology, the Netherlands R Berbeco Brigham And Women’s Hospital, Boston, USAW E Bolch University of Florida, Gainesville, USAT Bortfeld Massachusetts General Hospital, Boston, USAM E Brandan Mexico National Autonomous University (UNAM), Mexico City, MexicoA Bravin European Synchrotron Radiation Facility – Grenoble, FranceI Buvat INSERM, Paris, FranceG T Clement Cleveland Clinic, Cleveland, OH, USAM Danielsson KTH Royal Institute of Technology, Stockholm, SwedenY De Deene Macquarie University, AustraliaJ Deng Yale University, New Haven, CT, USAM M Doyley University of Rochester, NY, USA M Ebert Sir Charles Gairdner Hospital, Perth, AustraliaS B Fain University of Wisconsin, Madison, USAX Fan University of Chicago, IL, USAM Fix Bern University Hospital, SwitzerlandA Hirata Nagoya Institute of Technology, JapanK Hynynen University of Toronto, ON, CanadaT Inaniwa National Institute of Radiological Sciences, Chiba, JapanJ Izewska International Atomic Energy Agency – Vienna, AustriaO Jaekel DKFZ, Heidelberg, GermanyN Karssemeijer Radboud University Nijmegen Medical Centre, the NetherlandsP J Keall University of Sydney, AustraliaP E Kinahan University of Washington, Seattle, WA, USAZ Kuncic University of Sydney, Australia

R M Leahy University of Southern California, Los Angeles, USAJ S Lee Seoul National University, South KoreaA J Lomax Paul Scherrer Institute, Villigen, SwitzerlandN Matsufuji National Institute of Radiological Sciences, Chiba, JapanM McEwen Carleton University, Ottawa, CanadaW D Newhauser Louisiana State University, Baton Rouge, LA, USAU Oelfke Joint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, UKE Okada Keio University, Tokyo, JapanM Oldham Duke University, Durham, NC, USAH Paganetti Massachusetts General Hospital, Boston, USAM Partridge University of Oxford, UKM Rafecas University of Lubeck, GermanyN Ramanujam Duke University, Durham, NC, USAE M Sevick University of Texas Health Science Center, Houston, USAJ-J Sonke Netherlands Cancer Institute, Amsterdam, the NetherlandsM Tanter Institut Langevin, Paris, FranceJ Tian Chinese Academy of Sciences, Beijing, People’s Republic of ChinaV Tuchin Saratov State University, Russian FederationJ B Van de Kamer Netherlands Cancer Institute, Amsterdam, the NetherlandsG Van Rhoon Erasmus Medical Center, Rotterdam, the NetherlandsF Verhaegen Maastro Clinic, Maastricht, the NetherlandsL Xing Stanford University Medical Center, CA, USAX G Xu Rensselaer Polytechnic Institute, Troy, NY, USAN Yagi Japan Synchrotron Radiation Research Institute, Mikazuki, JapanM Zankl Helmholtz Centre, Munich, GermanyR Zemp University of Alberta, CanadaH Zheng Shenzhen Institute of Advanced Technology, People’s Republic of China

Editorial Board

P Gowland, University of Nottingham, UK

S R Cherry, University of California, Davis, USA

H Bosmans KU Leuven, Belgium P M Evans University of Surrey, Guildford, UK R Jeraj University of Wisconsin, Madison, USAS B Jiang University of Texas Southwestern Medical Center, Dallas, USAS R Meikle University of Sydney, Australia

X Pan University of Chicago, IL, USAK Parodi Ludwig-Maximilians University, Munich, GermanyB Pogue Dartmouth College, USAB Raaymakers University Medical Center, Utrecht, the Netherlands

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Discover more about the full range of IOP biosciences titles at ioppublishing.org/biosciences.

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Contents

To commemorate 60 years of PMB, the Editorial Board and International Advisory Boards of the journal have selected just 25 of the thousands of important works published in PMB that they felt have had a particular impact on the development of the field. In each case, we have asked the authors (or in cases where the authors were not available, an expert in the field) to explain the significance of the work. Please go to iopscience.org/pmb to read the full versions of all 25 papers.

The variation of scattered X-rays with density in an irradiated body 12J E O’Connor 1957 Phys. Med. Biol. 1 352

The theory of tracer experiments with 131I labelled plasma proteins 13Christine M E Matthews 1957 Phys. Med. Biol. 2 36

The performance of a gamma camera for the visualization of radioactive isotopes in vivo 14J R Mallard and M J Myers 1963 Phys. Med. Biol. 8 165

The partition of trace amounts of xenon between human blood and brain tissues at 37 °C 15N Veall and B L Mallett 1965 Phys. Med. Biol. 10 375

Reconstruction of densities from their projections, with applications in radiological physics 16A M Cormack 1973 Phys. Med. Biol. 18 195

Energy-selective reconstructions in X-ray computerised tomography 17R E Alvarez and A Macovski 1976 Phys. Med. Biol. 21 733

Computation of bremsstrahlung X-ray spectra and comparison with spectra measured with a Ge(Li) detector 18R Birch and M Marshall 1979 Phys. Med. Biol. 24 505

Fully three-dimensional positron emission tomography 19J G Colsher 1980 Phys. Med. Biol. 25 103

Spin warp NMR imaging and applications to human whole-body imaging 20W A Edelstein et al 1980 Phys. Med. Biol. 25 751

Basic mathematical and electromagnetic concepts of the biomagnetic inverse problem 21J Sarvas 1987 Phys. Med. Biol. 32 11

X-ray characterisation of normal and neoplastic breast tissues 22P C Johns and M J Yaffe 1987 Phys. Med. Biol. 32 675



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The generation of intensity-modulated fields for conformal radiotherapy by dynamic collimation 25D J Convery and M E Rosenbloom 1992 Phys. Med. Biol. 37 1359

A model for calculating tumour control probability in radiotherapy including the effects 26 of inhomogeneous distributions of dose and clonogenic cell density S Webb and A E Nahum 1993 Phys. Med. Biol. 38 653

Intensity-modulated arc therapy with dynamic multileaf collimation: an alternative to tomotherapy 28C X Yu 1995 Phys. Med. Biol. 40 1435

Respiration gated radiotherapy treatment: a technical study 29Hideo D Kubo and Bruce C Hill 1996 Phys. Med. Biol. 41 83

Adaptive radiation therapy 30Di Yan et al 1997 Phys. Med. Biol. 42 123

Simultaneous PET and MR imaging 32Yiping Shao et al 1997 Phys. Med. Biol. 42 1965

Intensity modulation methods for proton radiotherapy 34A Lomax 1999 Phys. Med. Biol. 44 185

Correlation between CT numbers and tissue parameters needed for Monte Carlo simulations 36 of clinical dose distributions Wilfried Schneider et al 2000 Phys. Med. Biol. 45 459

Treatment planning for heavy-ion radiotherapy: physical beam model and dose optimization 37M Krämer et al 2000 Phys. Med. Biol. 45 3299

Motion adaptive x-ray therapy: a feasibility study 38P J Keall et al 2001 Phys. Med. Biol. 46 1

GATE: a simulation toolkit for PET and SPECT 40S Jan et al 2004 Phys. Med. Biol. 49 4543

Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept 42B W Raaymakers et al 2009 Phys. Med. Biol. 54 N229

Evaluation of sparse-view reconstruction from flat-panel-detector cone-beam CT 44Junguo Bian et al 2010 Phys. Med. Biol. 55 6575

Time-of-flight PET data determine the attenuation sinogram up to a constant 46Michel Defrise et al 2012 Phys. Med. Biol. 57 885

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The variation of scattered X-rays with density in an irradiated body

J E O’Connor

1957 Phys. Med. Biol. 1 352

Abstract It is shown that, provided the effective atomic number remains constant, there is a general relationship between the variation of scatter with density and the variation with geometry of the system. A simplified analysis of the scatter contribution in water equivalent bodies is presented. This analysis leads to the definition of relative scatter absorption factors and the values of these factors in water equivalent materials are found by experiment for radiation with a half-value layer of 1.5 mm Cu. By the application of the general relationship between density of the body and geometry of the system values of the relative scatter absorption factors in bodies of other than unit density are deduced. These values may be employed in the calculation of the scatter dose delivered to points which lie in an inhomogeneous body. The practical importance of the results obtained is discussed with particular reference to the use of Transit Dose techniques.

This paper was selected for inclusion in the collection by Steven Meikle, Professor of Medical Imaging Physics at the University of Sydney in Australia. Meikle describes his reasons for choosing this particular work: “This paper reported the first detailed theoretical analysis and experimental validation of scatter ratios in an irradiated body. This was a problem of practical importance in X-ray imaging and external-beam radiotherapy.”

The author, J E O’Connor, tackled the calculation of dose delivered by scattered radiation to a point in an inhomogeneous body – a more complex problem than calculating dose delivered by the primary X-ray beam. In particular, the paper describes the calculation of the scattered dose contribution in materials with a different density to water, such as lung tissue.

The main scientific breakthrough described in this paper, explains Meikle, was the development of the theory that described the relationships between the geometry and density of an irradiated body on the one hand, and the scatter-to-primary absorption ratios on the other hand. The paper was of particular importance before the development of computerized dose calculation algorithms. Indeed, some early computerized dose calculation systems basically applied the same methodology.

As the calculations described in this paper are broadly applicable to any irradiated body (with extrapolation from homogeneous to inhomogeneous bodies), they are therefore still relevant to the estimation of absorbed dose in modern X-ray imaging and external-beam radiotherapy systems. For this

Differing densities: this figure from the paper illustrates the conditions when an X-ray beam is directed laterally through the thorax, through regions of differing density. Use of scatter correction factors (which can range from 0.7 for points in the centre of the lungs to 0.95 for points in the centre of the body, for example, the oesophagus) results in the reduction of the dose estimate obtained by using simple transit dose techniques.

reason, the paper continues to be cited regularly today, with 25 citations since 2000.

“This development laid the basis for methods of dose calculation in heterogeneous tissues and mixed radiation fields – problems that continue to be of practical importance in modern medical physics,” says Meikle. “Although more advanced methods for calculating absorbed dose have since been developed, such as Monte Carlo calculations, analytical codes are still used in clinical practice that rely on the underlying theory described in this paper.”

http://iopscience.iop.org/article/10.1088/0031-9155/1/4/305

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The theory of tracer experiments with 131I-labelled plasma proteins

Christine M E Matthews


Abstract Using the tracer theory of Rescigno, adapted for an open mammillary system, a method is given of finding (1) metabolic rate, (2) ratios of masses of protein in extravascular compartments to mass of protein in intravascular compartment, (3) capillary permeabilities, when 131I-labelled protein is injected into the blood stream of animals. Examples are given for human, rabbit and rat.

This paper describes a method for determining the metabolic rate, the ratios of the masses of protein in extravascular compartments to intravascular compartment, and the capillary permeabilities when 131I-labelled protein is injected into the blood stream. The author, Christine Matthews, presented examples for human, rabbit and rat.

“This is one of the early PMB papers concerning the theory and experiments on tracer kinetics and compartmental models. It contains basic ideas and presents models and tools that form the basis of modern tracer kinetic studies, for example, in dynamic PET and SPECT imaging,” explains Xiaochuan Pan, Professor of Radiology, Radiation and Cellular Oncology at the University of Chicago, who selected this paper.

“I like this article because it contains nicely formulated theoretical models and analysis supported by experimental (human and animal) data, because it was succinctly written and because it covered an important area of PMB readership interest,” says Pan. “The author exercised a high level of rigor in presenting/interpreting the results and in drawing conclusions.” The study also received the highest number of citations among articles published in the 1950s.

Based upon his knowledge of, and exposure to, tracer kinetic modelling and dynamic imaging, Pan believes that the general approach and models adopted in modern tracer kinetic research and applications, especially in the context of dynamic PET/SPECT imaging, remain largely and especially conceptually similar to those reported in the paper.

Tracer experiments: total activity in plasma compartment and derived total activity in extravascular compartments (obtained from cumulative excreted activity), after injection of 131I-labelled albumin into a human. The graph, taken from the original paper, also shows the metabolic rate.

He notes that the study is significant for medical physics today. “The development and validation of the approach reported in the paper has, in my opinion, a clear impact on today’s medical dynamic imaging, especially molecular imaging, research and application, including tracer-compartmental theory, kinetic parameter determination and parametric-image estimation,” he says.


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The performance of a gamma camera for the visualization of radioactive isotopes in vivo

J R Mallard and M J Myers


Abstract A prototype gamma camera for visualizing the distribution of radioactivity in vivo has been investigated and improved. Performance figures are given for each parameter that has been changed, to serve as a guide for practical applications and future development of the instrument. The camera differs from that of Anger mainly in that the display is presented on a storage tube; some advantages of this method of display are given.

This study provided the first published experimental evaluation of the performance of a gamma camera. The authors, Melvyn Myers and John Mallard, established the experimental procedures required to measure gamma camera performance parameters, as well as demonstrating agreement between theory and experiment.

“The main scientific breakthrough described in this paper was the formal introduction and practical description of a device based on an electronic, as opposed to mechanically scanning, principle that allowed localization, quantitative evaluation and time-varying visualization of organ function,” says Myers.

“I think that this paper was influential in two respects,” adds Steven Meikle from the University of Sydney in Australia, who selected this paper for

the collection. “Firstly, it led the way in establishing the experimental procedures for evaluating the performance of radiotracer imaging systems. Secondly, it demonstrated the unique performance characteristics of the gamma camera and its clear sensitivity advantage over other technologies available at the time.”

The gamma camera was invented in 1958, only a few years prior to this publication. And although the technology has undergone many advances since then – from the simple device described in the paper to four-dimensional whole-body imaging – the same basic principles apply to the design of modern SPECT systems. As such, this paper is still regularly cited, with 29 citations since 2000. “The work laid the basis for digital image processing as a new technique,” says Myers.

Myers and Mallard published a second paper alongside this one, outlining the clinical uses of the gamma camera. This companion study demonstrated the gamma camera’s potential clinical applications, some of which are still relevant today. “The scintillation camera has, for the past 40 years been the mainstay of organ function (as opposed to anatomic) imaging,” Myers explains. “This paper helped to support and expand the field of nuclear medicine, alongside complementary imaging techniques of CT and MRI and PET.”

Myers describes the impact of the publication on the two authors. “For John Mallard, this was one of a number of new developments (with others including MRI, cyclotrons and SPECT) that he recognized and encouraged for their potential importance,” he explains. “For myself, the experience in the new technology allowed both research and practical work in the IAEA and New York, and in senior positions in the UK over a period of nearly 50 years. It certainly launched me off on a long career and I am very grateful to John Mallard for having the foresight to pick up an idea of Hal Anger and run with it.”

Gamma camera head unit: the gamma camera may be considered as an analogue of a pinhole camera; y-rays take the place of light rays, a 1/16-3/8" diameter hole in heavy alloy takes the place of the pinhole, and a sodium iodide crystal replaces the photographic plate.


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The partition of trace amounts of xenon between human blood and brain tissues at 37 °C

N Veall and B L Mallett

1965 Phys. Med. Biol. 10 375

Abstract The relative solubilities of trace amounts of 133Xe at 37 °C in human plasma, red blood cells, grey and white matter of the brain, and in homogenized whole brain have been determined. From these data the tissue/blood partition coefficients for cortex, white matter and whole brain have been calculated as a function of haematocrit. On the basis of the measured 133Xe solubilities it is estimated that the human brain consists of 60.3 ± 6.3% grey matter and the remainder white matter.

This study by N Veall and B L Mallett reported a method for calculating the relative solubilities of 133Xe tracer in human blood and brain tissues and, from these measurements, derived tissue-to-blood partition coefficients, which are required to calculate blood flow in tissues from in vivo imaging data.

“The paper had a significant impact on the field of imaging with freely diffusible tracers, including more recent studies using 15O-water and PET,” says Steven Meikle, from the University of Sydney in Australia, describing why he picked this paper for inclusion in the collection.

Meikle notes that, while the theory for determining whole organ or tissue blood flow using freely diffusible tracers was well established (by Kety and Schmidt) at the time this paper was published, its practical application lacked knowledge of the partition coefficients of tracers in various tissues including the brain.

“The Veall and Mallett paper addressed this gap,” he explains. “In doing so, it also described a practical method for calculating the relative grey and white matter volumes in the human brain”.

Xenon has been used extensively in medical imaging studies over the last six decades, both as a radioactive tracer (133Xe) to estimate perfusion in various organs and tissues and as a dynamic contrast agent in X-ray CT. Thus, says Meikle, this paper was useful to many researchers across a wide range of fields that use such techniques. For this reason, the paper continues to be cited regularly today.

He points out that this development laid the basis for methods of measuring blood flow and tissue perfusion in vivo using inhaled inert gases. Such techniques are still used today and require ongoing studies by medical physicists and engineers to optimize the modelling and quantification of such measurements.

Radioactivity measurements: (left) measurement of 133Xe solubility in tissue relative to air; (right) 133Xe brain/blood partition coefficients.


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Reconstruction of densities from their projections, with applications in radiological physics

A M Cormack

1973 Phys. Med. Biol. 18 195

Abstract The precise determination of body attenuation for X-rays or its stopping power for heavy charged particles, positron annihilation scanning, and, to a lesser extent, single gamma -ray scanning all contain the same mathematical problem, namely, to determine a density distribution in space from its known projections on to one or more planes. Present methods of solving this problem involve taking slices through the distribution and considering the projected densities to be line integrals along lines through the slices and then using Fourier transforms, or orthogonal expansions of the line integrals, or a matrix inversion to determine the density distribution. An alternative method enables the density to be inferred by integration. In addition, a generalization of the method to surface integrals is given and possible applications are suggested including an application to positron annihilation scanning.

“This visionary article by one of the Nobel prize winners for CT laid the groundwork for image reconstruction algorithm research for decades to come,” says Xiaochuan Pan from the University of Chicago, who recommended Allan Cormack’s paper for the collection. The paper describes the theoretical approaches, known at the time, for tomographic image reconstruction, reporting the works by Johan Radon and Fritz John on the reconstruction of a function from line- or plane-integrals, and making the results accessible to the medical imaging community. “What become known as the Radon transform formed the basis of the image reconstruction algorithm used currently in the majority of tomographic imaging devices,” explains Pan.

The article also identifies applications to absorption coefficient imaging (CT), proton imaging, and gamma-ray tomography (PET and SPECT), all of which have benefited greatly from practical image reconstruction algorithms developed from Radon’s work. The article’s main influence, says Pan, was reporting Radon’s inversion formula for obtaining a 2D function from knowledge of line-integrals over the function. This theory eventually led to the ubiquitous filtered back-projection algorithm.

Pan emphasizes the importance of this work to medical physics today: “The introduction of Radon’s work to medical physics influenced all aspects of tomographic imaging,” he says. “It is true that Radon’s work had existed already for almost 60 years, but this is perhaps one of the most important functions of applied science; namely, to identify and adapt existing techniques or theory for a particular purpose.”

Pan cites some notable quotes from Cormack’s

paper: “If, as is usually the case, it is desired to determine g [the two-dimensional image] throughout a region of the plane the procedure of rotating the sample about each point in the plane would be most inconvenient.” This quote points out that direct use of Radon’s formula would lead to a highly impractical tomographic imaging device. Cormack then reports the convolution-based inversion formula that John derived from Radon’s work, which can be applied to the more practical scan of rotating the sample (or CT gantry) once.

“The methods differ, sometimes controversially, in the manner in which the formidable number of linear equations is handled.” In this quote, Cormack was referring to iterative image reconstruction algorithms that were available at the time. More than 40 years later, Pan says, one can make the same statement about iterative image reconstruction.

“An obvious difficulty with this method is that, since it is best suited to objects of roughly spherical shape, it is not well suited to use on people!” Here, Cormack was referring to the possible use of Radon’s 3D image reconstruction formula for PET. The quote describes one of the major CT image reconstruction challenges: how to adapt Radon’s 3D inversion formula to helical CT imaging for non-spherical objects – such as people.

“It is difficult to say what would have happened without this article by Cormack,” concludes Pan. “It may be that someone else would have made the connection to Radon’s work within a year or two. Or maybe the connection would have been seen only much later. In this case, filtered back-projection may have only developed into a curiosity confined to academic circles.”


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Energy-selective reconstructions in X-ray computerised tomography

R E Alvarez and A Macovski

1976 Phys. Med. Biol. 21 733

Abstract All X-ray computerized tomography systems that are available or proposed base their reconstructions on measurements that integrate over energy. X-ray tubes produce a broad spectrum of photon energies and a great deal of information can be derived by measuring changes in the transmitted spectrum. It is shown that for any material, complete energy spectral information may be summarized by a few constants that are independent of energy. A technique is presented that uses simple, low-resolution, energy spectrum measurements and conventional computerized tomography techniques to calculate these constants at every point within a cross-section of an object.

This study by Robert Alvarez and Albert Macovski presents a technique that uses simple, low- resolution, energy spectrum measurements and conventional techniques to obtain energy-dependent information from a CT system. Compared with standard CT images, which are reconstructed based on measurements that integrate over energy, this approach can increase the diagnostic capabilities of the image.

“The main scientific breakthrough was the ability to create images of different body materials using X-ray measurements at different energies,” says Macovski. “The particular processing scheme created by my co-author, Robert Alvarez, was very significant.” Macovski suggests that the now universal use of energy-selective imaging by X-ray manufacturers is indicative of the value of this endeavour.

Since the paper was published, much effort has been applied to energy-selective detection methods and signal processing. “Investigators in X-ray imaging

Material-specific: (a) conventional chest image (a), a processed image showing only soft tissue (b) and a processed image showing only bone (c).

have seized on this general concept and applied it to both radiography and computerized tomography,” Macovski adds. “My particular recent effort has been in noise reduction.”

“This work enabled our medical imaging group to obtain a number of NIH [National Institutes of Health] grants, which facilitated our efforts and enabled us to explore other imaging modalities, namely MRI,” Macovski explains. “Dr Alvarez has continued to explore advanced research in this area and has become the world leader in energy-selective imaging.”


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Computation of bremsstrahlung X-ray spectra and comparison with spectra measured with a Ge(Li) detector

R Birch and M Marshall

1979 Phys. Med. Biol. 24 505

Abstract A method of computing theoretical X-ray spectra in the range 30–150 kV is presented. The theoretical spectra are compared with constant potential, high-resolution spectra from a tungsten target measured with a Ge(Li) detector, for a range of target angles, tube voltage and filtrations. Above 100 kV the spectra were also measured with a NaI detector but, as there was good agreement between the Ge(Li) and NaI detectors, only the former are presented. Spectra computed using Kramers’ theory are also included for comparison, giving fairly good agreement at large target angles (30°) but becoming gradually worse as the target angle decreased. Spectra may be computed by this method for any desired filtration, target angle, and tube voltage between 30 and 150 kV, in excellent agreement with the measured data.

In this work, R Birch and M Marshall identified and accounted for the main physical factors contributing to the spectral form of X-ray radiation generated by diagnostic X-ray sources. Their method, for example, accurately modelled beam filtration and accounted for absorption in a thick target. The model was also validated for a range of parameters encountered in X-ray imaging, such as X-ray energy, target angles, tube voltage, and filtration material and thickness.

“We selected this article because it really is the first work to present an accurate X-ray source spectrum model that applies to diagnostic X-ray imaging devices,” says Xiaochuan Pan from the University of Chicago. “As diagnostic X-ray has been and remains a major component of medical imaging the work has had widespread impact on the field.”

The X-ray source spectrum is needed for many clinical and research purposes in diagnostic imaging. X-ray dose calculations for diagnostic equipment rely

Data comparison: (solid line), the present work (dashed line) and Kramers’ theory (stars) at (left) 100 kVp with 10° target angle, (centre) 100 kVp with 30° target angle and (right) 140 kVp with 30° target angle, all with 2.55 mm Al total filtration.

on accurate models of the X-ray source spectrum. This is particularly important for mammography, where a large segment of the female population is being subjected to ionizing radiation for screening purposes. Knowledge of X-ray source spectrum is also a key factor in improving image quality through beam-hardening corrections or extracting additional diagnostic information from X-ray and CT imaging by use of dual-energy and multi-spectral methods.

“The authors were extremely careful and thorough in developing an accurate spectrum model for diagnostic X-ray sources,” says Pan. “Their model was employed nearly exclusively in the following decades for X-ray systems development and characterization. At present, other competing models have been developed, but the Birch–Marshall model still enjoys widespread use in medical imaging for clinical and research applications.”


19


Fully three-dimensional positron emission tomography

J G Colsher

1980 Phys. Med. Biol. 25 103

Abstract Fully three-dimensional positron emission tomography is considered and a reconstruction algorithm derived. The reconstruction problem is formulated mathematically as a three-dimensional convolution integral of a point spread function with an unknown positron activity distribution and is solved by Fourier transform methods. Performance of the algorithm is evaluated using both simulated phantom data produced by a Monte Carlo computer program and phantom data obtained from the University of Chicago/Searle Positron Camera. It is concluded that the method is computationally feasible and results in accurate reconstructions.

“The main scientific breakthrough described in this paper was the derivation of a reconstruction filter for 3D PET,” says the article’s author James Colsher. “A point spread function for a back-projected point is expressed in spherical coordinates and the inverse filter was derived using Fourier transform techniques.”

One of the earliest peer-reviewed papers on 3D PET, this paper has been widely cited – 226 times to date according to Google Scholar. “More importantly, I think that once an analytical solution to the filter was shown to exist, others started to work on 3D PET,” Colsher adds. “Paul Kinahan and Joel Rogers at TRIUMF developed a reprojection algorithm eliminating the need for a spatially invariant point spread function. Norbert Pelc published similar algorithms in his doctoral dissertation at Harvard. Simon Cherry and colleagues at UCLA performed 3D PET by removing the SEPTA from a commercial PET scanner.”

Following the publication of the paper, over 35 years ago, Colsher spent 27 years (1982–2009) employed as a scientist at GE Healthcare. For the first 10 years, he notes, GE was not involved in developing PET. “I worked in the Applied Science Laboratory on CT, concentrating on system design, calibration and reconstruction. When GE decided to explore commercialization of PET, I joined a small team chartered to answer the question: ‘Should GE enter the PET business?’ The answer was yes and I returned to doing research on PET. I was one of a few scientists at GE with experience in PET so I spent most of my time as ‘player-coach’.”

In 2001, Colsher moved to Durham, NC, and started working at Duke University while remaining

Improving the image: single section of reconstruction using computer-generated data; (a) back-projected image, (b) histogram of central line through (a), (c) filtered image, (d) histogram of central line through (c).

a GE employee. Capitalizing on his expertise in CT and PET, he worked on methods to reduce CT dose when CT is used only for attenuation correction of PET data. “In 2009, I retired and accepted an adjunct faculty position at Duke, where I now focus on CT dose reduction for both CT and PET/CT.”

When this paper was written, PET was performed by acquiring 2D projection data and reconstructing images using a 2D filtered back projection algorithm. Today PET is performed by acquiring 3D data and reconstructing images using 3D iterative reconstruction algorithms. “This change resulted from the cumulative contributions of many scientists, with this paper helping to lay the groundwork,” says Colsher.


20


Spin warp NMR imaging and applications to human whole-body imaging

W A Edelstein, J M S Hutchison, G Johnson and T Redpath

1980 Phys. Med. Biol. 25 751

Abstract This letter describes a new nuclear magnetic resonance (NMR) imaging technique that the authors call ‘spin warp imaging’ and gives examples of its application to human whole-body imaging. The apparatus is based on a four-coil, air cored magnet (made by the Oxford Instrument Company) capable of accepting the whole human body. The magnet produces a static field of 0.04 T giving a proton NMR frequency of 1.7 MHz. The maximum field inhomogeneity is about 6*10–4 at a radius of 0.23 m, approximately twice the amount theoretically attainable with this configuration. The pulse sequence used is shown.

This publication described the concept and implementation of phase-encoding in MRI. “This allowed a dramatic improvement in image quality and is still the imaging technique used by all clinical MRI scanners world-wide,” says author Thomas Redpath, from the University of Aberdeen, where this research was performed. “The paper also showed that whole-body MRI scanning was possible using existing hardware – other research groups were at that time capable of producing reasonable MRI quality in small animals, or the human brain.”

After the publication of this paper, Redpath concentrated on designing and building a number of RF receiving coils, and then quickly moved on to imaging sequence development. “Following that, I worked on developing and applying MRI methods for use in cardiac and cancer imaging,” he explains. “I was

MRI expert: Jim Hutchison with the 0.04 T Oxford Instruments electromagnet, which was the basis of the group’s MRI scanner. The photo is estimated to be from 1978, as there are no gradient or RF coils yet built in, nor the Faraday screen needed to shield the imager from interference.

Prime mover: Bill Edelstein in the computer room at the University of Aberdeen’s Department of Medical Physics, with the DEC mini-computer used to reconstruct images by applying a 2D fast Fourier transform to the raw complex data. The photo was taken in 1980.

in the first year of my PhD when the group made this breakthrough – it meant that my entire subsequent career was in MRI.”

Redpath says that “spin-warp” as they called it, or phase-encoding as it came to be known, was a fundamental breakthrough – both in its concept and in its practical application. Spin-warp allowed images with much improved signal-to-noise ratios, and with greatly minimized image artefacts, to be obtained, in very much shorter image acquisition times.

Redpath notes that Bill Edelstein, who died in February 2014, was the prime mover behind spin-warp. “However, without the electronic, engineering and magnetic resonance expertise of Jim Hutchison, the group would not have been able to demonstrate the practical value of the theoretical breakthrough,” he adds.


21


Basic mathematical and electromagnetic concepts of the biomagnetic inverse problem

J Sarvas


Abstract Basic mathematical and physical concepts of the biomagnetic inverse problem are reviewed with some new approaches. The forward problem is discussed for both homogeneous and inhomogeneous media. Geselowitz’ formulae and a surface integral equation are presented to handle a piecewise homogeneous conductor. The special cases of a spherically symmetric conductor and a horizontally layered medium are discussed in detail. The non-uniqueness of the solution of the magnetic inverse problem is discussed and the difficulty caused by the contribution of the electric potential to the magnetic field outside the conductor is studied. As practical methods of solving the inverse problem, a weighted least-squares search with confidence limits and the method of minimum norm estimate are discussed.

“I wrote this as a review paper to extend my talk in a conference on biomagnetic inverse problems in the previous year,” says Jukka Sarvas of his 1987 publication. “I am a mathematician and at that time, as also later, I was quite familiar with electromagnetic field computing tasks. But my experience with biomagnetic problems was somewhat limited, though I had already been working a couple of years on the field computing and interpretation of the MEG measurements in the Helsinki University of Technology.”

As such, he notes that learning more about this research was one of his incentives for writing the review paper with “more personal work and contribution than, perhaps, it is usual for review papers”.

Sarvas thinks that the main significance of the paper was to review the basic MEG field computing concepts and formulas in a unified and mathematically clarified form, which later became very much the standard in those questions. In particular, he says, for application to the spherical head model, which still has a large practical use in approximating the MEG and EEG fields.

“What really made the paper very much cited was a new result in the spherical head model, presenting a closed form formula for the magnetic field outside the spherical head due to an electric dipole in the head,” Sarvas explains. “The formula is in no way revolutionary, but very handy in numerical field computing with the spherical head model. And

Electromagnetism expert: Jukka Sarvas in 1986.

frankly speaking, I was later quite surprised that the formula became so well-known.”

In his later career, Sarvas has mostly been working on other fields of applied mathematics and statistics than bioengineering, but he says that it has always been nice to follow the increasing citation numbers of the 1987 PMB paper.

“After my research position from 1984–86 in the Helsinki University of Technology (presently called Aalto University), I had other academic positions in Finland, and in 2003 came back to the Helsinki University of Technology as a professor in computational electromagnetism,” Sarvas says. “I retired in 2007, and thereafter returned back to my old 1987 field in brain research by MEG and EEG, and have worked as a part-time supervisor for PhD students in the department of Neuroscience and Biomedical Engineering in Aalto University.”


22


X-ray characterisation of normal and neoplastic breast tissues

P C Johns and M J Yaffe

1987 Phys. Med. Biol. 32 675

Abstract Normal and neoplastic breast tissues have been characterized in terms of X-ray attenuation. Samples of normal fat and fibrous tissue were obtained from reduction mammoplasty and autopsy, and infiltrating duct carcinoma specimens from mastectomy and lumpectomy. A high-purity germanium spectroscopy system and a beam of 120 kV constant potential X-rays were used to determine the linear attenuation coefficient from 18 to 110 keV. Densities were determined from buoyancy measurements and were used to obtain mass attenuation coefficients. Infiltrating duct carcinomas and fat are well distinguished by X-ray attenuation. For photon energies used for film-screen mammography, infiltrating duct carcinomas are more attenuating than fibrous tissue. Above 31 keV, the ranges of attenuation of the two tissue types overlap. The attenuation coefficients of tissues have been concisely represented by equivalent thicknesses of lucite and aluminium. Analysis based on the average attenuation properties of tissues indicates that dual-energy mammography, using an ideal imaging system, would require 0.06 cGy to provide images in which 1 cm infiltrating duct carcinomas are displayed with a signal to noise ratio of 5 against a background over which the fat/fibrous contrast has been suppressed. This dose is similar to that currently used in conventional film-screen mammography.

This study was performed to address the lack of precise data on the X-ray attenuation properties of breast tissue, explains co-author Martin Yaffe. “My student at the time, Paul Johns, now Professor of Physics at Carleton University in Ottawa, and I, set out to conduct such measurements,” he says. “We worked with a pathologist, who helped us obtain tissue samples in which the individual components: fibroglandular tissue, fat and breast tumour, were isolated.”

Johns designed a precise apparatus that allowed a very narrow X-ray beam to be created, and he and Yaffe employed a germanium solid-state X-ray spectrometer to perform very careful transmission measurements through the sample. “Special attention was required in determining the thickness of the tissue sample,” says Yaffe. “Paul actually had to develop some new theory (which was published separately in Nuclear Instruments and Methods) on X-ray pulse counting, to correct for the high count rates in the experiment.”

Yaffe adds that these measurements are important as they were used by his own group, as well as many other scientists internationally, in calculations related to breast imaging with X-rays, radiation safety, dosimetry, detector design, risk estimation and other applications.

“I hope that the reason this paper was selected was because it provided very useful and practical information to many researchers, who used the data for their own important projects,” says Yaffe. “I also hope that there was an appreciation for the extreme care that was required in making precise and accurate measurements.”

The original team: Paul Johns (far left) and Martin Yaffe (second from left) are in the front row, along with Sandra Stapleton (now a consultant in medical image processing) and Curtis Caldwell (now a scientist at Sunnybrook). In the back row (left to right) are Normand Robert (currently research associate at Sunnybrook), Rebecca Fahrig (who recently left a position as Associate Professor at Stanford University to join Siemens in Germany), Robert Nishikawa (now Professor in Radiology at the University of Pittsburgh), Andrew Maidment (now Associate Professor of Radiology at The University of Pennsylvania) and Jeffrey Byng (now an executive at Carestream Health).


23


In conducting this work and obtaining successful results, Johns had to “move away from the clean and comfortable world of physics into the messy world of tissue from surgical specimens” and had to learn to work with professionals in this area. “I think that being able to work in a multidisciplinary manner greatly amplifies the impact that physicists can have in contributing to the fields of medicine and biology,” Yaffe adds.

Following this work, Yaffe launched a large effort on the development of digital mammography. Naturally, he used the results from this paper to inform many of his calculations. “I have also worked in designing quality control test tools and methods for radiological imaging and on the quantification of mammographic density as an estimator of the risk of developing breast cancer,” he says. “Most recently, I

Side view of the apparatus: the lead-shielded X-ray tube is on the left, the specimen holder and alignment mechanism in the centre, and an intrinsic germanium solid-state X-ray spectrometer with its liquid nitrogen cooling Dewar on the right.

have circled back to bring many of the techniques of quantitative imaging into the pathology laboratory. Overall, I have published over 250 peer-reviewed papers, many of which utilized data from our ‘X-ray characterization’ paper.”

Yaffe describes the impact that this work had on his career: “I believe that I learned a lot from this work about how to do accurate measurements. I have used the results of this work hundreds of times in subsequent projects leading to other published papers. Both Paul and I have been thanked by other researchers for having published these data. This is very gratifying.”

“In recognition of my research on breast cancer I will be inducted into The Order of Canada next month.”


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25


The generation of intensity-modulated fields for conformal radiotherapy by dynamic collimation

D J Convery and M E Rosenbloom

1992 Phys. Med. Biol. 37 1359

Abstract An algorithm has been developed to calculate the collimator jaw motions required to generate intensity-modulated fields for use in conformal radiotherapy. The dynamic technique allows arbitrary intensity profiles to be generated using a single unidirectional sweep of the collimators. The collimator jaws have independent motion, so that an aperture of variable width is scanned across the field. The algorithm has the form of a constrained optimization problem and jaw motions are optimized such that the treatment time for the field at a given dose rate is minimized. The application and results of this technique are presented, and it is shown that this approach provides an efficient practical implementation of conformal radiotherapy plans based on the use of intensity-modulated fields. The technique can be extended to 3D treatment plans and fields through the use of computer-controlled multileaf collimators.

“This paper was the first publication to show how intensity-modulated fields may be delivered in practice using a multileaf collimator (MLC),” says Philip Evans, Professor of Medical Radiation Imaging at the University of Surrey, UK, who recommended this paper for inclusion.

The authors, D J Convery and M E Rosenbloom, achieved this by presenting the fundamental algorithm that uses the single unidirectional leaf sweep, Evans explains. This work has influenced many subsequent studies, but above all has provided the basis for intensity-modulated radiotherapy (IMRT) that is used in the clinic today,” he says.

“Prior to this work, there were several published studies on the concept of IMRT, but these did not provide a solution to the problem of how such a treatment may be delivered in practice,” says Evans. “In addition, these earlier studies generally considered a beam delivery that was a set of static fields. This was the first solution to the problem of delivering a beam with the MLC leaves moving during radiation, resulting in a more efficient and accurate dose delivery.”

At the time of this paper’s publication, whilst the concept of IMRT already existed, there were several outstanding problems to be solved. Firstly, existing approaches considered the technique known as

step-and-shoot, where treatment is delivered as a set of apertures. This work demonstrated a more elegant approach that involved moving the leaves of the collimation system during beam delivery.

Secondly, there was the question of deliverability. No one had yet carried out IMRT in practice. This work provided the method that would dominate IMRT delivery and is the basis of the modern approach.

Evans emphasizes that this technique became the basis of all IMRT delivered with a linear accelerator equipped with an MLC. “There have been many subsequent studies that have refined the delivery of IMRT with an MLC. These include modelling detailed radiation leakage effects and developing methods to make leaf sequencing more efficient, but these all rely on the foundation of the original Convery and Rosenbloom work,” he explains.

“Modern cancer treatment with radiation, in the vast majority of cases, relies on this technique to deliver the dose profile to the patient. This technique has been implemented by manufacturers, which has enabled clinical trials that have shown clinical benefit from IMRT in a range of common cancers. Without this work these trials would not have happened or at least would have happened much later,” says Evans.


26


A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density

S Webb and A E Nahum

1993 Phys. Med. Biol. 38 653

Abstract Most calculations of the biological effect of radiation on tumours assume that the clonogenic cell density is uniform even if account is taken of non-uniform dose distribution. In practice, tumours will almost certainly have a non-uniform clonogenic cell density. The paper extends one particular model of tumour control probability (TCP) to incorporate a variable clonogenic cell density while at the same time assuming a constant 2 Gy fraction size and a uniform radiosensitivity throughout the treatment. Since there are virtually no in vivo data on the variation of density the authors consider some model situations. One clear conclusion is that a large reduction in clonogenic cell density at the edges of a tumour would permit only a very modest decrease in dose if the TCP is not to be reduced. In general the effect on TCP is a complicated function of the variation in both dose and clonogenic cell density. The authors give the equations which enable both to be included.

“We developed a practical, easy-to-evaluate mathematical model for tumour control probability (TCP) incorporating the maximum amount of well-established radiobiology including, importantly, inter-patient differences in radiosensitivity, individual tumour volume, and a methodology to handle dose-volume histogram (DVH) data on heterogeneous tumour doses (from 3D treatment-planning systems),” say co-authors Steve Webb and Alan Nahum, reflecting on their 1993 paper.

They emphasize that this was the first such model to combine what was known about tumour-cell radiobiology with data from 3D treatment plans, in such a way that clinical outcomes could be simulated based on realistic assumptions about clonogen radiosensitivity, number and distribution.

“The fundamental equation predicting TCP from uniformly irradiating a volume to a specific dose had been published a little earlier in the ART91 (Munich) conference proceedings,” they explain.

“Our PMB paper was the first publication of the above model in a peer-reviewed journal. Furthermore, the paper included the generalization of this equation to subvolumes with different doses and different clonogenic cell densities. After integration over the whole tumour volume (including an outer loop over the (patient) tumour population with varying radiosensitivity), the Webb-Nahum TCP model, subsequently known as the ‘Marsden’ model, enabled (local) TCP to be evaluated for arbitrary inhomogeneous dose distributions in inhomogeneous tissues.”

The paper, which has now been cited almost 400 times – along with normal-tissue complication probability (NTCP) modelling – helped to spawn the whole subfield of (radio)biological modelling, which bridged the gap between laboratory-based radiobiology (cell-survival curves, for example) and clinical radiotherapy treatment planning.

Following publication of this paper, Webb used the methodology to re-visit and fit some data from David Brenner. He also worked with Bill Swindell, Phil Evans and Joe Deasy to completely generalize the appendix in the Webb-Nahum paper (which proved that uniform dose maximizes TCP for fixed integral dose). Subsequently, he turned his attention away from radiobiology.

The research performed by Nahum’s team progressed onto isotoxic tumour dose individualization (initiated in the ART91 paper), the effect of heterogeneous doses, the BIOPLAN and Co-authors: Steve Webb (left) and Alan Nahum.


27


BioSuite (free) software, re-visiting the seminal work on the correlation between tumour radiosensitivity (from biopsies) and clinical outcome by Catharine West, the incorporation of hypoxia (thanks to Don Chapman when Nahum was at Fox-Chase), the Clatterbridge radiobiology course (2006–2015), Eva Rutkowska’s LQ-based NTCP model (with Colin Baker), the (α/β)eff concept (with Aswin Hoffmann, though its genesis was an invited ICTR talk in Lugano in 2003) and a radiobiologically-based determination of the treatment-plan margin size (Jothybasu Selvaraj).

From working in this area for the next two decades, Nahum has co-authored 59 papers on radiobiological modelling to date. However, “our 1993 paper has not had the impact than I had hoped for”, he notes. “Particularly disappointing has been the lukewarm interest by commercial treatment-planning companies in incorporating radiobiological modelling into their products.” “There have been a decent number of related research papers but still, 22 years later, papers appear based on TCP models with no σα parameter (the parameter embodying the population-averaging of tumour-clonogen radiosensitivity α) and implausible best-fit parameters,” he adds.

Nahum suggests that the TCP part of radiobiological modelling remains a “Cinderella” subfield, with low interest shown by the majority of clinical radiation-therapy physicists. “Things are somewhat better regarding NTCP modelling,” he notes, “thanks to the magnificent efforts of the Milan-based research team (Fiorino, Rancati, Cattaneo, Calandrino and colleagues) on rectal complication modelling and the NKI (Amsterdam) group (Lebesque, Seppenwoolde, De Jaeger, Mijnheer and colleagues) on radiation pneumonitis modelling. The vocational, Department-of-Health-funded Liverpool University MSc (started 2011) has a substantial radiobiology content due to my efforts.”

Nahum says that the impact of this paper on his career was incalculable. “It opened up a whole new research direction, bringing me into contact with eminent radiobiologists such as Don Chapman and Jack Fowler, a number of brillant PhD students, and postdoctoral researchers Beatriz Sanchez-Nieto, Stefano Gianolini and Julien Uzan.”

“For eight years, I lectured on TCP modelling on the Amsterdam-based ESTRO IMRT course (1998–2005). I set up and ran the Clatterbridge four-day course ‘Radiobiology & Radiobiological Modelling in Radiotherapy’, which ran from 2006 to 2015. With its international faculty (including Chapman and Fowler, as well as Roger Dale, Trevor McMillan, Ellen Yorke, Giovanna Gagliardi, Marco Schwarz, Hooshang Nikjoo, Catharine West, John Fenwick, Wolfgang Tomé and Andrzej Kacperek), it attracted

delegates from all over the world.” “Clatterbridge radiation oncologist Isabel

Syndikus, physicist Julien Uzan and I developed the BioProp prostate tumour intensity-modulated-dose-painting protocol; two CR UK-funded ‘isotoxic’ phase-II clinical trials of non-small-cell lung cancer radiotherapy (IDEAL-CRT, designed by former PhD student John Fenwick and radiation oncologist David Landau, and I-START, developed by radiation oncologists Jason Lester (Velindre RT centre, Cardiff), Nazia Mohamed (Glasgow), Zafar Malik and Eswar Chinnamani (Clatterbridge) and physicists John Fenwick and myself) built on the radiobiological modelling work initiated at ICR-Royal Marsden and continued at Clatterbridge Cancer Centre and Liverpool university.”

Recently, Nahum co-authored the book “Radiotherapy Treatment Planning: Linear-Quadratic Radiobiology” with legendary experimental radiobiologist Chapman. “Probably none of the above would have happened without the Webb-Nahum 1993 paper,” he notes.

For Webb, the paper’s impact was less significant. “This was because, from 1994 onwards until my retirement in 2011, my radiation-therapy physics interests focused almost exclusively on 3D radiation dose planning and optimization, methods to deliver 3D conformal radiotherapy and intensity-modulated radiation therapy (IMRT) and methods for compensation for tumour motion,” he explains.

“I wrote a quartet of single-author books between 1993 and 2004 documenting the international progress in these areas, as well as my contribution. For 14 years I supervised the teaching of advanced radiation-therapy physics at the EFOMP/ESI School in Archamps, Geneva. My main international collaborations were with DKFZ, Heidelberg, led by Wolfgang Schlegel and Thomas Bortfeld (now at MGH), as well as several collaborations with accelerator manufacturers.

Radiological approach: the potential of radiotherapy treatment plan optimization based on tumour control probability (TCP) and normal-tissue complication probability (NTCP). The right NTCP curve corresponds to a highly conformal plan (for example, protons) and the left one to a standard linac X-ray plan. Switching from X-rays to protons would increase the TCP from just under 50% to around 90% (image from Nahum and Uzan 2012 Computational and Mathematical Methods in Medicine doi: 10.1155/2012/329214).


28


Intensity-modulated arc therapy with dynamic multileaf collimation: an alternative to tomotherapy

C X Yu

1995 Phys. Med. Biol. 40 1435

Abstract The desire to improve local tumour control and cure more cancer patients, coupled with advances in computer technology and linear accelerator design, has spurred the developments of three-dimensional conformal radiotherapy techniques. Optimized treatment plans, aiming to deliver high dose to the target while minimizing dose to the surrounding tissues, can be delivered with multiple fields each with spatially modulated beam intensities or with multiple-slice treatments. The author introduces a new method, intensity-modulated arc therapy (IMAT), for delivering optimized treatment plans to improve the therapeutic ratio. It utilizes continuous gantry motion as in conventional arc therapy. Unlike conventional arc therapy, the field shape, which is conformed with the multileaf collimator, changes during gantry rotation. Arbitrary two-dimensional beam intensity distributions at different beam angles are delivered with multiple superimposing arcs. A system capable of delivering the IMAT has been implemented. An example is given that illustrates the feasibility of this new method. Advantages of this new technique over tomotherapy and other slice-based delivery schemes are also discussed.

In this paper, Cedric X Yu, Professor of Radiation Oncology at the University of Maryland School of Medicine, describes the implementation of a new radiotherapy modality: intensity-modulated arc therapy (IMAT). The technique combines spatial and temporal intensity modulation with movement of the gantry.

“The quality of a radiation treatment depends on the utilization of the available degrees of freedom for the specific anatomy. Such utilization is presented by the total number of independent ‘quanta’, or apertures used for the treatment,” explains Yu. “This knowledge or realization allows more efficient radiation treatment delivery by rotating the radiation beam around the target while varying the aperture shapes. As a result, the treatment time is reduced from over 10 minutes to under two minutes.”

The efficiency advantage of this approach led to its rapid and widespread clinical adoption all over the world. Of all the cancer patients receiving radiation treatments today, more than half are being treated using rotational intensity modulation methods first proposed by this paper. “By making optimal photon treatment more efficient, it allowed more patients to receive such treatments, even in developing countries,” says Yu.

Yu explains that further advancements of radiation therapy require the enhanced abilities to

Shaping the dose: example treatment plan used to deliver IMRT to a C-shaped target partially surrounding a circular critical structure (left). The isodose distribution is superimposed on one CT slice of the test phantom. The inner and outer isodose contours on the target are 90% and 80%, respectively; the inner and outer isodose contours on the critical structure are 10% and 20%, respectively. The delivered dose distributions (right), with light areas representing high-dose regions and dark areas low-dose regions.

deliver better dose distributions. “While many in the field have switched their focus onto different forms of radiation, such as protons, I have been focusing my efforts on ways to increase the degrees-of-freedom using photon beams, through site-specific solutions and new radiation treatment machine designs,” he says. “One of my new inventions, the GammaPod – a breast-specific treatment device – is under clinical study.”

“This paper showed me that an innovative idea can make a practical impact on many lives,” Yu adds. “It has propelled me along a career path of technology innovation.”


29


Respiration gated radiotherapy treatment: a technical study

Hideo D Kubo and Bruce C Hill


Abstract In order to optimize external-beam conformal radiotherapy, patient movement during treatment must be minimized. For treatment on the upper torso, the target organs are known to move substantially due to patient respiration. This paper deals with the technical aspects of gating the radiotherapy beam synchronously with respiration: the optimal respiration monitoring system, measurements of organ displacement and linear accelerator gating. Several respiration sensors including a thermistor, a thermocouple, a strain gauge and a pneumotachograph were examined to find the optimal sensor. The magnitude of breast, chest wall and lung motion were determined using playback of fluoroscopic x-ray images recorded on a VCR during routine radiotherapy simulation. Total dose, beam symmetry and beam uniformity were examined to determine any effects on the Varian 2100C linear accelerator due to gating.

According to Steve Jiang, who chose this paper for the collection, this work by Hideo Kubo and Bruce Hill represents a milestone in the radiation treatment of moving targets.

“In radiotherapy of cancer patients, you want the tumour to be still during treatment otherwise you miss it. If you miss it, you will have some tumour cells remaining and you won’t be able to cure the cancer; you will also deliver radiation dose to normal tissue and critical structures,” explains Jiang, professor in the Department of Radiation Oncology at the University of Texas Southwestern Medical Center.

But there’s a challenge: respiratory motion. In the lung, liver and abdominal regions, a tumour may move quite a lot as the patient breathes. This has been a major challenge in radiotherapy: how do you treat a moving target?

“The old way to do this was to use a large margin,” explains Jiang. “But then you harm a lot of normal tissue. These two authors came up with the idea that if I know where the tumour is, then I just turn on the radiation beam when it is in the right position and turn it off when it’s not there – this is gating.”

So how do you determine where the tumour is? Breathing is periodical, so if the breathing signal can be measured to determine the phase information, then the beam can be turned on during the exhale period, and turned off at other times. “Kubo and Hill developed methods to measure the breathing signal. Now this technology has become standard for moving targets like lung cancer and liver cancer,” says Jiang.

“Their paper was the first, that’s why I picked it, it solved a very important problem,” he adds. And as the

Breathe deep: panel A shows schematic respiration signals and the optimal gate voltage at which the treatment beam should be turned on – the “window” provides a higher beam-on duty cycle. Panel B shows desirable respiration signals that may be obtained with the use of a breath-hold device; the beam-on duty cycle is increased considerably compared with that in panel A.

first, opening the door for this new technology, this paper has had hundreds of citations.

Gating is now a standard technology in radiotherapy. “If the motion is not too large, there are other options, you can use a bigger beam,” explains Jiang. “But if the motion is big, gating is the most popular solution. Some people use abdominal compression but that’s not very popular. You can track a tumour with an MLC [multileaf collimator], that is just being developed. But the real practical and popular technology is gating.”


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Adaptive radiation therapy

Di Yan, Frank Vicini, John Wong and Alvaro Martinez

1997 Phys. Med. Biol. 42 123

Abstract Adaptive radiation therapy is a closed-loop radiation treatment process where the treatment plan can be modified using a systematic feedback of measurements. Adaptive radiation therapy intends to improve radiation treatment by systematically monitoring treatment variations and incorporating them to re-optimize the treatment plan early on during the course of treatment. In this process, field margin and treatment dose can be routinely customized to each individual patient to achieve a safe dose escalation.

Changes in patient position, organ and tumour geometry, and biological activities during the course of radiotherapy are intrinsic, inevitable and directly related to the treatment response. “This paper described the importance and the necessity of using a closed-loop feedback process to systematically adapt the changes to optimize radiation treatment,” says author Di Yan, Chief of Physics at Beaumont Health System.

The paper outlines a process to replace conventional open-loop radiotherapy by a closed-loop feedback adaptive treatment process. The authors discuss a typical adaptive optimization strategy on patient geometric variation, including

assessment of the individual patient treatment position variation, individualized target margin design and optimization.

As for the impact of this work, “this paper has significant influence on the study, technology development and clinical applications of adaptive radiotherapy during the last 18 years,” says Yan. “It has promoted significantly the clinical implementations and technology development for image guidance and treatment adaptation. Most importantly, adaptive radiotherapy is becoming a new treatment standard for radiotherapy.”

Since the paper was published, Yan and colleagues have been working on many research projects,

Adaptive treatment modification: ART interface showing the original plan dose (top left) and the adapted plan (top right).


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Closed-loop approach: flowchart showing the image feedback adaptive control system for radiotherapy.

supported by the National Cancer Institute (NCI) and by industry, along with performing clinical trials on adaptive radiotherapy. “An image feedback adaptive treatment system integrated with an in-house adaptive image suite – including CT, onboard cone-beam CT, PET/CT, MRI and 4D ultrasound – has been developed and implemented in the clinic for clinical adaptive treatment,” Yan explains.

The paper also had a big influence on Yan’s future career. “My works in adaptive radiotherapy have been well known in the radiation oncology community,” he says. “I have been rewarded by numbers of NCI and industrial research grants on the study and development of adaptive radiotherapy, and also invited as a speaker for many international scientific conferences.”


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Simultaneous PET and MR imaging

Yiping Shao, Simon R Cherry, Keyvan Farahani, Ken Meadors, Stefan Siegel, Robert W Silverman and Paul K Marsden

1997 Phys. Med. Biol. 42 1965

Abstract We have developed a prototype PET detector which is compatible with a clinical MRI system to provide simultaneous PET and MR imaging. This single-slice PET system consists of 48 2 x 2 x 10 mm3 LSO crystals in a 38 mm diameter ring configuration that can be placed inside the receiver coil of the MRI system, coupled to three multi-channel photomultipliers housed outside the main magnetic field via 4 m long and 2 mm diameter optical fibres. The PET system exhibits 2 mm spatial resolution, 41% energy resolution at 511 keV and 20 ns timing resolution. Simultaneous PET and MR phantom images were successfully acquired.

This paper described the development and evaluation of, arguably, the first integrated functional (PET) and anatomic (MRI) dual-imaging modality, with simultaneous imaging acquisition capability, says lead author Yiping Shao, Professor in Radiation Oncology at the University of Texas Southwestern Medical Center.

“In my humble opinion,” adds Shao, “the main reason for this honourable selection is the significance of this paper to the subsequent development of various integrated multi-modality imaging technologies, including commercialized PET/MR systems, and the important and increased impact of these technologies to the biomedical and medical researches and applications.”

Following publication of this work, integrated PET/MR imaging has been established as a stand alone research field, with approximately 100 installed commercialized PET/MR systems worldwide, and a series of dedicated international conferences on this subject. In addition, Shao points out, integrated multi-modality imaging applications have since been actively researched and applied with different functional and anatomic imaging modalities – notably PET/CT, SPECT/CT and SPECT/MR

imaging. This further expanded and advanced imaging technology development for molecular imaging and other applications.

“If the impact of this work to the field were not immediately expected fully, the impact of this work to my career development was clear and profound even during this work,” says Shao. “It was a research project with a multidisciplinary team attempting a groundbreaking study with imaginations, novel ideas and innovative detector technology developed at that time.”

“As a postdoctoral fellow, I was very fortunate by having an opportunity to lead the project, supported by my mentor Simon Cherry,” Shao adds. “I benefited immensely from learning new technical skills and gaining research experience. The success of this work had catalysed my research career, and the development of advanced PET imaging technologies for novel imaging and therapy applications has remained as my research theme since then.”

“Since this paper was published, many subsequent important research progresses of simultaneous PET/MR imaging have been made by Simon Cherry’s lab, along with other research groups and companies,” says Shao.

Back in the days: the research team (from left to right) Stefan Siegel, Simon Cherry, Randal Slates, Keyvan Farahani, Yiping Shao and Robert Silverman.

Initial set-up for simultaneous imaging: the PET detector ring is inside the MRI receiving coil, while the PMTs and electronics are outside of the MRI.


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Prototype system: the detector ring (on the blue surface) consists of 48 lutetium oxyorthosilicate (LSO) crystals, each connected via optical fibre to a pixel of a multi-channel photomultiplier.

A closer look: the 38 mm diameter detector ring consists of 48 2 x 2 x 10 mm lutetium oxyorthosilicate (LSO) crystals.


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Intensity modulation methods for proton radiotherapy

A Lomax

1999 Phys. Med. Biol. 44 185

Abstract The characteristic Bragg peak of protons or heavy ions provides a good localization of dose in three dimensions. Through their ability to deliver laterally and distally shaped homogenous fields, protons have been shown to be a precise and practical method for delivering highly conformal radiotherapy. However, in an analogous manner to intensity modulation for photons, protons can be used to construct dose distributions through the application of many individually inhomogeneous fields, but with the localization of dose in the Bragg peak providing the possibility of modulating intensity within each field in two or three dimensions. We describe four different methods of intensity modulation for protons and describe how these have been implemented in an existing proton planning system. As a preliminary evaluation of the efficacy of these methods, each has been applied to an example case using a variety of field combinations. Dose-volume histogram analysis of the resulting dose distributions shows that when large numbers of fields are used, all techniques exhibit both good target homogeneity and sparing of neighbouring critical structures, with little difference between the four techniques being discerned. As the number of fields is decreased, however, only a full 3D modulation of individual Bragg peaks can preserve both target coverage and sparing of normal tissues. We conclude that the 3D method provides the greatest flexibility for constructing conformal doses in challenging situations, but that when large numbers of beam ports are available, little advantage may be gained from the additional modulation of intensity in depth.

“This paper was the first to show the power of optimization and ‘inverse planning’ methods to proton therapy,” says its author Tony Lomax, Chief Medical Physicist at the Paul Scherrer Institute in Switzerland. “As such, I believe it showed the potential flexibility and clinical power of pencil beam scanned (PBS) proton therapy and put it in the context of IMRT [intensity-modulated radiotherapy] for conventional radiotherapy.”

Lomax thinks that his paper may have been chosen for the collection because of the rapidly growing interest in, and clinical implementation of, PBS proton therapy. “This has had the consequence that an increasing number of facilities and research groups now have access to PBS proton therapy facilities and planning systems, and are also thus currently exploring the research and clinical potential of this modality,” he says.

The article showed the radiotherapy community that PBS proton therapy was very likely the future of proton therapy. “IMPT [intensity-modulated proton therapy] is inherently flexible and brings the same level of planning and delivery automation as IMRT brought for conventional therapy,” Lomax explains. “In short, it showed that PBS could be a more

Planning example: dose distributions for nine regularly spaced non-parallel opposed fields with 2D (left) and 3D (right) modulated plans, which represent the worst and best methods, respectively, for this beam arrangement.

powerful, practical and easier approach to highly conformal proton therapy than was/is possible with passive scattered proton therapy.”

Since this paper was published, the research group has achieved routine implementation of IMPT into the clinic, together with the first outcome analysis of patients treated with this approach.

“At a more theoretical level, we have expanded on the work by looking into the relationship of IMPT and plan robustness (the sensitivity, or lack thereof, of the plan to delivery uncertainties),” Lomax adds. “We are also currently working on applying IMPT techniques to mobile tumours in the form of 4D optimization.”


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PSI en masse: the proton therapy group at the Paul Scherrer Institute, around 1999.

Time out: Tony Lomax is Chief Medical Physicist at the Paul Scherrer Institute in Switzerland.

Lomax says that the publication certainly helped progress his career opportunities. “In any career, it helps to have visibility, and this paper brought me that, at first in the proton therapy community and then in the wider radiotherapy community as well,” he explains. “However, it is also easier to make an impact when one is working in a bit of a niche field, and I am incredibly lucky that I found myself working in such a niche in the late 1990s when I did this work. It is always easier being a ‘big fish’ in a ‘small sea’, and this is exactly what I became after this paper.”


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Correlation between CT numbers and tissue parameters needed for Monte Carlo simulations of clinical dose distributions

Wilfried Schneider, Thomas Bortfeld and Wolfgang Schlegel

2000 Phys. Med. Biol. 45 459

Abstract We describe a new method to convert CT numbers into mass density and elemental weights of tissues required as input for dose calculations with Monte Carlo codes such as EGS4. As a first step, we calculate the CT numbers for 71 human tissues. To reduce the effort for the necessary fits of the CT numbers to mass density and elemental weights, we establish four sections on the CT number scale, each confined by selected tissues. Within each section, the mass density and elemental weights of the selected tissues are interpolated. For this purpose, functional relationships between the CT number and each of the tissue parameters, valid for media which are composed of only two components in varying proportions, are derived. Compared with conventional data fits, no loss of accuracy is accepted when using the interpolation functions. Assuming plausible values for the deviations of calculated and measured CT numbers, the mass density can be determined with an accuracy better than 0.04 g cm–3. The weights of phosphorus and calcium can be determined with maximum uncertainties of 1 or 2.3 percentage points (pp) respectively. Similar values can be achieved for hydrogen (0.8 pp) and nitrogen (3 pp). For carbon and oxygen weights, errors up to 14 pp can occur. The influence of the elemental weights on the results of Monte Carlo dose calculations is investigated and discussed.

The three authors of this paper – Wilfried Schneider, Thomas Bortfeld and Wolfgang Schlegel – devised a simple yet sufficiently accurate method of converting CT numbers to elemental weights, which are required for all Monte Carlo-based dose calculations. According to author Thomas Bortfeld, the work resulted essentially as a by-product in a project on electron dose calculation.

“We don’t know why the paper was selected for the collection, but we are thrilled about it!” says Bortfeld, Chief of Physics Division at Massachusetts General Hospital’s Department of Radiation Oncology. “It reminds us of good old times when we all worked together at the German Cancer Research Center. Perhaps it was selected because it so clearly stood the test of time and it actually appears to become more relevant with time. The paper was virtually ignored in the first three years after its publication in 2000, but it received 60 citations in 2015 alone and hasn’t peaked yet.”

The method described in this work has been used as the basis for many Monte Carlo dose calculation

methods, with the increasing implementation of Monte Carlo dose calculation for radiation therapy definitely increasing the demand for this method. “We hope that our work has indirectly helped to improve many patient treatments through more accurate dose calculation,” says Bortfeld.

Since the paper was published, the authors’ research has progressed in different directions, none related to this paper. “It is perhaps a strength of this work that it stands on its own and doesn’t require many follow-up improvements to make it work better or work at all,” Bortfeld adds.

Team of three: (left to right) Wilfried Schneider, Thomas Bortfeld and Wolfgang Schlegel.


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Treatment planning for heavy-ion radiotherapy: physical beam model and dose optimization

M Krämer, O Jäkel, T Haberer, G Kraft, D Schardt and U Weber

2000 Phys. Med. Biol. 45 3299

Abstract We describe a novel code system, TRiP, dedicated to the planning of radiotherapy with energetic ions, in particular 12C. The software is designed to cooperate with three-dimensional active dose shaping devices like the GSI raster scan system. This unique beam delivery system allows us to select any combination from a list of 253 individual beam energies, 7 different beam spot sizes and 15 intensity levels. The software includes a beam model adapted to and verified for carbon ions. Inverse planning techniques are implemented in order to obtain a uniform target dose distribution from clinical input data, i.e. CT images and patient contours. This implies the automatic generation of intensity modulated fields of heavy ions with as many as 40 000 raster points, where each point corresponds to a specific beam position, energy and particle fluence. This set of data is directly passed to the beam delivery and control system. The treatment planning code has been in clinical use since the start of the GSI pilot project in December 1997. Forty-eight patients have been successfully planned and treated.

This paper describes the basic principles of the computer code TRiP (TReatment planning for Particles), created for planning carbon ion treatments.

“Scanned beams of carbon ions for radiotherapy were a novelty back then,” says author Michael Krämer, from the GSI Helmholtz Centre for Heavy Ion Research in Darmstadt, Germany. “Therapy planning for this then new modality, comprising physical and radiobiological modelling as well as three-dimensional optimization including the relative biological effectiveness, was also novel.”

Krämer notes that since the paper was a pioneering one in its field, many follow-up publications might have used it as a reference, hence its selection for this collection.

Following on from the publication of this paper, large advances have been made across the entire field of ion beam radiotherapy. “We have also made progress, refining our models and procedures,” says Krämer. “The associated software, TRiP98, is still one of the standard tools in this field. Eventually, we were able to transfer our research from a pilot project to standard clinical use.”

All of the authors have continued their work in the field of ion beam radiotherapy and are currently working as senior scientists, professors or directors.

Clinical plan: the calculated absorbed dose distribution for a patient after optimization, (a) in the water-equivalent system in the beam’s-eye view on a line through the isocentre, and (b) graphed on top of a CT image slice through the isocentre. The isodose lines correspond to 10, 20, 50, 80 and 95%.

As the first paper describing in sufficient detail the ingredients of therapy planning for scanned carbon ions, this work serves as a reference for future researchers, says Krämer. He also points out that a companion paper to this work was published in the same issue (Phys. Med. Biol. 45 3319). “The other article is about the radiobiological aspects of the problem, which are of equal importance,” he explains. “Back then we decided to treat the two aspects in two separate manuscripts, but scientifically, they belong together.”


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Motion adaptive x-ray therapy: a feasibility study

P J Keall, V R Kini, S S Vedam and R Mohan


Abstract Intrafraction motion caused by breathing requires increased treatment margins for chest and abdominal radiotherapy and may lead to ‘motion artefacts’ in dose distributions during intensity modulated radiotherapy (IMRT). Technologies such as gated radiotherapy may significantly increase the treatment time, while breath-hold techniques may be poorly tolerated by pulmonarily compromised patients. A solution that allows reduced margins and dose distribution artefacts, without compromising delivery time, is to synchronously follow the target motion by adapting the x-ray beam using a dynamic multileaf collimator (MLC), i.e. motion adaptive x-ray therapy, or MAX-T for short. Though the target is moving with time, in the MAX-T beam view the target is static. The MAX-T method superimposes the target motion due to respiration onto the beam originally planned for delivery. Thus during beam delivery the beam is dynamically changing position with respect to the isocentre using a dynamic MLC, the leaf positions of which are dependent upon the target position. Synchronization of the MLC motion and target motion occurs using respiration gated radiotherapy equipment. The concept and feasibility of MAX-T and the capability of the treatment machine to deliver such a treatment were investigated by performing measurements for uniform and IMRT fields using a mechanical sinusoidal oscillator to simulate target motion. Target dose measurements obtained using MAX-T for a moving target were found to be equivalent to those delivered to a static target by a static beam.

The main scientific breakthrough of this paper was that it was the first experimental demonstration that the multileaf collimator (MLC) – a very common tool in cancer radiotherapy – could be used to target tumours as they moved during treatment.

“At the time when this work was being performed, the late 1990s and early 2000s, the challenges of tumour motion and particularly respiratory-induced tumour motion were beginning to be understood, and approaches to manage this motion were starting to be developed,” explains author Paul Keall, currently a Professor at the University of Sydney and Director of the Radiation Physics Laboratory. “This paper was

one of the earliest to directly demonstrate that tumour tracking was feasible.”

Since the 2001 paper, Keall and colleagues have been continually focused on the bench-to-bedside clinical translation of this technology. Their research has progressed from algorithmic advances, through experimental investigations, quality assurance programme development and, in 2013, on to patient treatments for prostate cancer. Most recently, towards the end of 2015, the team began a clinical trial using a MLC to track moving lung tumours during radiation therapy.

“This paper is one of many that have raised the

Tracking team: (left to right) Paul Keall, Sastry Vedam, V Kini and Radhe Mohan.


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awareness of target motion and the development of strategies to manage motion, either explicitly by moving the beam (or the patient) to follow the target, or implicitly via margins or probabilistic planning,” Keall explains. “From these works, the field of ‘4D radiotherapy’ has emerged, which has remained one of the most important areas of radiation oncology research for over a decade.”

Based on this work, and other investigations into respiratory motion management, Keall received funding – initially from the US National Cancer Institute, and also equipment and funding from Varian Medical Systems – to advance the experimental investigations. “This success translated

Clinical first: one of the world’s first lung cancer patients to be treated with the MLC tracking technology that stemmed from this work.

into academic promotion and career advancement,” he says.

“Our research team has continued to pursue MLC tracking and through this work I have been fortunate to have been invited to many institutions and conferences around the world to present on different aspects of the evolving research programme,” Keall adds. “With the translation of the technology into clinical prostate and lung cancer trials, knowing that technology I have helped create is being used to improve the treatment of patients is incredibly satisfying and one of the highlights of my career to date.”


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GATE: a simulation toolkit for PET and SPECT

S Jan, G Santin, D Strul, S Staelens, K Assié, D Autret, S Avner, R Barbier, M Bardiès, P M Bloomfield, D Brasse, V Breton, P Bruyndonckx, I Buvat, A F Chatziioannou, Y Choi, Y H Chung, C Comtat, D Donnarieix, L Ferrer, S J Glick, C J Groiselle, D Guez, P-F Honore, S Kerhoas-Cavata, A S Kirov, V Kohli, M Koole, M Krieguer, D J van der Laan, F Lamare, G Largeron, C Lartizien, D Lazaro, M C Maas, L Maigne, F Mayet, F Melot, C Merheb, E Pennacchio, J Perez, U Pietrzyk, F R Rannou, M Rey, D R Schaart, C R Schmidtlein, L Simon, T Y Song, J-M Vieira, D Visvikis, R Van de Walle, E Wieërs and C Morel

2004 Phys. Med. Biol. 49 4543

Abstract Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http://www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

“Our paper described a recently released open source software dedicated to Monte Carlo simulations for emission tomography and enabling a very broad range of simulations, which were not covered by any other software at that time,” says author Christian Morel, from the Centre de Physique des Particules de Marseille, Aix-Marseille Université and CNRS/IN2P3 in France. “The fact that this new software was based on Geant4, an already existing and well-validated toolbox developed at CERN for high-energy physics, was certainly very important to guarantee that the physics models used in the software were sound.”

Morel suggests that this paper was probably selected for the collection due to its importance to the community of emission tomography scientists, and on medical physics at large. “A large number of groups involved in medical imaging research and in therapy based on ionizing radiation are now using GATE for Design simulations: the GATE ClearPET/XPAD design, which led to

the construction of the prototype.

all sorts of applications – from designing prototypes up to validating methods to extracting quantitative parameters from images – and therefore refer to our paper that describes the code,” he explains.

Due to the early success of GATE in the emission tomography research community, Morel and co-


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Completed device: the ClearPET/XPAD prototype, presented at the 2015 IEEE Nuclear Science Symposium and Medical Imaging Conference.

authors have continued to develop the code, adding more and more features over time. As such, GATE can now model far more than just emission tomography, but can also simulate radiation therapy, transmission tomography and optical imaging experiments.

“Since the first version described in the 2004 article, 19 enhanced versions have been released to extend the application field of the software,” says Morel. “While welcoming new developers who contribute to original developments in the code, we are currently introducing additional features and preparing future releases as imaging is evolving fast. Our goal is to make the code appropriate for modelling today’s imaging concepts and devices.”

“We are pleased to see that the GATE software as it was described in this article has been well received by the community and is now part of the tools that scientists and companies rely on when doing research in emission tomography,” Morel adds. “Obviously, GATE is useful to the emission tomography community and our article played an important role in disseminating its description, which was precisely the goal of our initiative.”

Morel explains that the GATE specifications were originally defined to assist the development of prototypes of a small-animal PET scanner called ClearPET, developed by the Crystal Clear collaboration. The decision to foster long-term support and maintenance of GATE by sharing this code development among many research groups, and to create the OpenGATE collaboration for this purpose, proved astute.

“Retrospectively, the setting up and organization of the development of GATE within the OpenGATE collaboration, which consists of a worldwide community of colleagues sharing common objectives on a goodwill basis, initially in absence of dedicated funding, resulted in a most – if not the most – exciting and joyful period of my career, and hopefully of the career of most of my co-authors,” says Morel. “For me, it certainly contributed to my academic career development, since I was appointed as a Professor at the University of Aix-Marseille shortly after the publication of the 2004 PMB article.”


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Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept

B W Raaymakers, J J W Lagendijk, J Overweg, J G M Kok, A J E Raaijmakers, E M Kerkhof, R W van der Put, I Meijsing, S P M Crijns, F Benedosso, M van Vulpen, C H W de Graaff, J Allen and K J Brown

2009 Phys. Med. Biol. 54 N229

Abstract At the UMC Utrecht, The Netherlands, we have constructed a prototype MRI accelerator. The prototype is a modified 6 MV Elekta (Crawley, UK) accelerator next to a modified 1.5 T Philips Achieva (Best, The Netherlands) MRI system. From the initial design onwards, modifications to both systems were aimed to yield simultaneous and unhampered operation of the MRI and the accelerator. Indeed, the simultaneous operation is shown by performing diagnostic quality 1.5 T MRI with the radiation beam on. No degradation of the performance of either system was found. The integrated 1.5 T MRI system and radiotherapy accelerator allow simultaneous irradiation and MR imaging. The full diagnostic imaging capacities of the MRI can be used; dedicated sequences for MRI-guided radiotherapy treatments will be developed. This proof of concept opens the door towards a clinical prototype to start testing MRI-guided radiation therapy (MRIgRT) in the clinic.

In this breakthrough paper, Bas Raaymakers and colleagues at UMC Utrecht in the Netherlands proved that MRI and linac-based radiotherapy could be performed simultaneously, with 1.5T MR imaging possible during radiation delivery. Prior to this publication, the magnetic and radiofrequency interaction between an MRI and a linac was considered so destructive that such simultaneous performance was not possible.

“The concept of offering sight to the radiation oncologist is very appealing,” says Raaymakers.

“MRI can visualize and track virtually all types of tissues. This study opened a new field of research, dosimetry in a magnetic field, but also it boosted the development of work towards real-time adaptive radiotherapy, as the MRI-linac can offer the real-time anatomical updates needed for this.”

Raaymakers says that the paper was the stimulus needed for Elekta to upgrade the prototype system, enabling the Utrecht team to extend the proof-of-concept from simultaneous MRI and radiation delivery of a simple block-defined square field,

Commercial launch: Bas Raaymakers (left), with Elekta Service Engineer Robert Spaninks, in front of Elekta’s Atlantic MRI-guided radiotherapy system, due be launched in 2017. Image credit: PRNews Foto/Elekta.

http://iopscience.iop.org/article/10.1088/0031-9155/54/12/N01

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to the proof of performing intensity-modulated radiotherapy (IMRT) and MRI-based gating and tracking. “Extensive dosimetric evaluation has also been done, plus work towards real-time adaptive radiotherapy and the development of dedicated MRI sequences for MRI-guided radiotherapy,” he adds. “And of course, work towards clinical implementation of this technology.”

The MRI-linac concept has been developed in collaboration with Elekta and Philips, and is now being commercialized by Elekta as its next-generation radiotherapy system. Also, an international academic and industrial consortium has been formed – with Elekta, Philips, UMC Utrecht, MD Anderson Cancer Clinics, ICR and the Royal Marsden, Netherlands Cancer Institute Antoni van Leeuwenhoek, the Christie, Sunnybrook Health Sciences Center and the Froedtert & Medical College of Wisconsin – to guide and jointly perform the clinical introduction of this technology.

“The promise of real-time anatomical feedback opens a new direction for radiotherapy, we aim for radiosurgical approaches for any tumour site, while maintaining the existing benefits of radiotherapy to treat microscopic infiltrations,” Raaymakers

Hands-on approach: Bas Raaymakers working on the installation of the prototype MRI-accelerator back in 2009. Image credit: Jan Kok.

explains. He notes that the concept of hybrid MRI radiotherapy systems is now also being adopted by other groups, such as the company ViewRay, the Edmonton group of Gino Fallone and the MRI-linac program of the University of Sydney.

Raaymakers says that this paper had a large impact on his career. “I have been involved right from the start, together with Jan Lagendijk,” he explains. “This is a kind of dream scenario: a goofy idea that becomes a multi-million commercial product and a large international academic consortium to demonstrate the added clinical value.”

He notes that many research papers are now addressing all kinds of topics related to MRI-linac development, ranging from MRI-specific work, dosimetry and adaptive planning to clinical studies on MRI-based delineations for on-line usage. “That makes you feel proud,” says Raaymakers. “Also, the UMC Utrecht appreciated the impact by assigning me full professor in experimental clinical physics. I will happily proceed research around the clinical implementation, real-time MRI-based adaptive radiotherapy, and see how to exploit these advances for other radiotherapy modalities such as proton therapy.”

http://iopscience.iop.org/article/10.1088/0031-9155/54/12/N01

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Evaluation of sparse-view reconstruction from flat-panel-detector cone-beam CT

Junguo Bian, Jeffrey H Siewerdsen, Xiao Han, Emil Y Sidky, Jerry L Prince, Charles A Pelizzari and Xiaochuan Pan

2010 Phys. Med. Biol. 55 6575

Abstract Flat-panel-detector x-ray cone-beam computed tomography (CBCT) is used in a rapidly increasing host of imaging applications, including image-guided surgery and radiotherapy. The purpose of the work is to investigate and evaluate image reconstruction from data collected at projection views significantly fewer than what is used in current CBCT imaging. Specifically, we carried out imaging experiments using a bench-top CBCT system that was designed to mimic imaging conditions in image-guided surgery and radiotherapy; we applied an image reconstruction algorithm based on constrained total-variation (TV)-minimization to data acquired with sparsely sampled view-angles and conducted extensive evaluation of algorithm performance. Results of the evaluation studies demonstrate that, depending upon scanning conditions and imaging tasks, algorithms based on constrained TV-minimization can reconstruct images of potential utility from a small fraction of the data used in typical, current CBCT applications. A practical implication of the study is that the optimization of algorithm design and implementation can be exploited for considerably reducing imaging effort and radiation dose in CBCT.

This work investigates an image reconstruction algorithm – called ASD-POCS (adaptive steepest descent-projection onto convex sets) – that exploits sparsity in the scanned subject to allow a reduced numbers of X-ray projections to be used. The paper demonstrates the algorithm on experimentally collected cone-beam CT (CBCT) images. While standard practice calls for 500 to 1000 X-ray projections to be collected, this paper showed that useful results could be obtained using only 30 to 96 X-ray projections for the study conditions.

“The potential of such an algorithm can be exploited for reduced imaging time or radiation dose for existing CBCT devices,” explain authors Junguo Bian and Xiaochuan Pan from the University of Chicago. “A broader implication of the work lies in the possibility that the algorithm may be designed and implemented for enabling novel scanning configurations, imaging systems or workflow tailored to specific applications, which cannot be realized otherwise with current scanning systems.”

In the paper, the authors investigate the possibility of reducing the number of projections in CBCT by a factor of 10 or more for special circumstances where the subject is spatially sparse, such as in blood vessel imaging. A more general approach for projection view reduction, applicable to the majority of medical imaging, was then developed and demonstrated

Head phantom reconstructions: images reconstructed from 60-view and 96-view data sets using the FDK, EM, POCS and ASD-POCS algorithms, within transverse, coronal and sagittal slices. The last column displays the FDK-reference images within the corresponding slices. Low-contrast tumour structures can be observed in the ASD-POCS reconstructions and FDK-reference images.

in computer simulation for CBCT. “We feel that this paper was possibly selected for the collection because it demonstrates the latter approach with real experimental data, and presents results of practical implications for brain imaging,” say Bian and Pan.

Since the paper was published, Bian and Pan have continued their research on the optimization-based methods used in this paper for CBCT and other imaging modalities, including digital breast


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Imaging a cylindrical phantom: images reconstructed from 30-view data sets using the FDK, EM, POCS and ASD-POCS algorithms, within transverse, coronal and sagittal slices. The central region of the transverse slice is re-displayed with a zoomed-in view to show a wire insert. The last column is the FDK-reference images within the corresponding slices.

tomosynthesis, phase-contrast CT and positron-emission tomography. “We have acquired since then a great deal of knowledge of and insight into optimization-based reconstruction, and have explored its implication for some practical applications of interest to medical imaging,” they say.

They note that the paper may have been instrumental in influencing researchers to consider sparsity-exploiting image reconstruction for CT and other tomographic systems. An important aspect of such reconstruction algorithms is that standard

evaluation techniques may not be meaningful, and as a result, many of the evaluation techniques used in the paper have been adopted by other researchers.

“The success of this work has influenced the direction of our research as there are many possibilities realizing new tomographic devices following upon the presented methodology,” add Bian and Pan. “As a result, we have focused more on translational research, developing image reconstruction algorithms to enable new clinical applications for tomographic imaging.”


46


Time-of-flight PET data determine the attenuation sinogram up to a constant

Michel Defrise, Ahmadreza Rezaei and Johan Nuyts

2012 Phys. Med. Biol. 57 885

Abstract In positron emission tomography (PET), a quantitative reconstruction of the tracer distribution requires accurate attenuation correction. We consider situations where a direct measurement of the attenuation coefficient of the tissues is not available or is unreliable, and where one attempts to estimate the attenuation sinogram directly from the emission data by exploiting the consistency conditions that must be satisfied by the non-attenuated data. We show that in time-of-flight PET, the attenuation sinogram is determined by the emission data except for a constant and that its gradient can be estimated efficiently using a simple analytic algorithm. The stability of the method is illustrated numerically by means of a 2D simulation.

In PET, quantitative reconstruction of the tracer distribution requires accurate attenuation correction. In some situations, however, a direct measurement of the attenuation coefficient of the tissues by X-ray CT is not available or is unreliable, for instance due to patient motion. In this paper, Michel Defrise from Vrije Universiteit Brussel, and Ahmadreza Rezaei and Johan Nuyts from the Katholieke Universiteit Leuven, proved that in time-of-flight (TOF) PET, the attenuation coefficients and tracer distribution can be determined using just the emission data, except for a multiplicative constant.

“While it had previously been shown empirically that the TOF-PET data contain significant information on the attenuation, the mathematical proof and the numerical illustration in this paper provided a firm ground for the development of quantitative PET without or with limited anatomical data,” explains Defrise. “One application is in the fast developing field of multimodality TOF-PET/MR imaging.”

“The numerical example in the paper was a proof-of-principle using an analytic algorithm,” says Defrise. “In emission tomography, however, better reconstructions are obtained with iterative algorithms. Based on previous works for non-TOF-PET, we implemented and tested on simulated and clinical TOF-PET data, three different algorithms

Clinical data: a clinical PET scan with the tracer 18FDG showing, for each case, a transaxial, frontal and sagittal section. Left: standard PET-CT procedure using the CT data (top) for attenuation correction of the tracer activity (bottom). Right: simultaneous reconstruction of the attenuation (top) and activity (bottom) using only emission data and the MLAA [maximum likelihood reconstruction of attenuation and activity] algorithm.

based on the maximization of the likelihood with respect to both attenuation and activity in TOF-PET.”

“In the four years since its publication, this paper has fostered works by several groups aiming at improving TOF-PET quantitation when reliable and complete attenuation data are not available,” says Defrise. Progress has also been made for attenuation correction of gated TOF-PET data synchronized with the respiratory or cardiac phase. “Clinical application will require further evaluation, as well as finding reliable solutions to estimate the multiplicative scaling factor required to obtain absolute quantitation of the PET tracer concentration,” Defrise explains.



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