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B E S T O F

CONTENTS INTRODUCTION FROM THE EDITORS-IN-CHIEF ARTICLES IN FULL 1. COMMENTARY

2. COMMENTARY

3. REVIEW ARTICLE

10.1259/bjr.20140416

10.1259/bjr.20130629

10.1259/bjr.20130662

Next steps and barriers to implementing lung cancer screening with low-dose CT. D R Baldwin, E L O’Dowd

What we know and what we don’t know about cancer risks associated with radiation doses from radiological imaging. D J Brenner

Adult post-mortem imaging in traumatic and cardiorespiratory death and its relation to clinical radiological imaging. B Morgan, D Adlam, C Robinson, M Pakkal, G N Rutty

4. FULL PAPER

7. REVIEW ARTICLE

10. REVIEW ARTICLE

10.1259/bjr.20140477

10.1259/bjr.20140547

10.1259/bjr.20130685

iPad-based primary 2D reading of CT angiography examinations of patients with suspected acute gastrointestinal bleeding: preliminary experience.

A review of performance of nearinfrared fluorescence imaging devices used in clinical studies.

DNA DSB repair pathway choice: an orchestrated handover mechanism.

ARTICLE EXCERPTS

L Faggioni, E Neri, I Bargellini, P Scalise, F Calcagni, A Mantarro, G D’Ippolito, C Bartolozzi

8. FULL PAPER

10.1259/bjr.20150025

10.1259/bjr.20140150

Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries.

Medial temporal lobe atrophy in Alzheimer’s disease/mild cognitive impairment with depression.

T S Emrich, K Emrich, N Abegunewardene, K Oberholzer, C Dueber, T Muenzel, K-F Kreitner

5. SHORT COMMUNICATION

V Dhikav, M Sethi, K S Anand

6. FULL PAPER

10.1259/bjr.20130163 Effects of a difference in respiratory cycle between treatment planning and irradiation for phase-controlled rescanning and carbon pencil beam scanning. S Mori, T Inaniwa, T Furukawa, S Zenklusen, T Shirai, K Noda

A Kakarougkas, P A Jeggo

B Zhu, E M Sevick-Muraca

11. SHORT COMMUNICATION

10.1259/bjr.20140325 MR simulation for prostate radiation therapy: effect of coil mounting position on image quality. J Sun, P Pichler, J Dowling, F Menk, P Stanwell, J Arm, P B Greer

12. FULL PAPER

10.1259/bjr.20140428 9. FULL PAPER

10.1259/bjr.20130496 Mammographic and clinicopathological features of triple-negative breast cancer. B Gao, H Zhang, S-D Zhang, X-Y Cheng, S-M Zheng, Y-H Sun, D-W Zhang, Y Jiang, J-W Tian

Vaginal displacement during course of adjuvant radiation for cervical cancer: results from a prospective IG-IMRT study. S Chopra, A Patidar, T Dora, N Moirangthem, S N Paul, R Engineer, U Mahantshetty, S K Shrivastava Read the excerpts in full with the online access code on page 4.

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BJR is essential reading for radiologists, medical physicists, radiotherapists, radiographers and radiobiologists. Articles included in BJR cover a wide range of subjects, including diagnostic radiology, radiotherapy, oncology, nuclear medicine, ultrasound, radiation physics, radiation protection and radiobiology.

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BJR’s international impact continues to grow… with articles received from over 90 countries in the last year.

DAVID BRADLEY Editor-in-Chief (Scientific)

NIGEL HOGGARD Editor-in-Chief (Medical)

BJR is an international, multidisciplinary journal covering medical imaging, radiation oncology, medical physics, radiobiology and the underpinning sciences. This latest collection of articles contains a cross-section of the broad, multidisciplinary content that can be found in BJR. Featured articles include a commentary on implementing lung cancer screening with low-dose CT, a radiobiologist’s perspective on what we know and don’t know about cancer risks associated with radiological imaging and a comprehensive review on adult post-mortem imaging and its relation to clinical radiology. Find out how you can get free access to read these articles in full on the next page. It’s been an exciting and busy period for BJR, including the publication of three successful special features, covering radiobiology, forensic radiology and brachytherapy dosimetry, with more themed content coming soon. Look out for special issues on advances in radiotherapy, nanoparticles and interventional musculoskeletal procedures. BJR’s international impact continues to grow and our international editorial board is delighted to see increasingly global submissions, with articles received from over 90 countries in the last year. We’re also excited to be engaging with the community in new ways, including our ever-popular cover competition and growing social media presence. Our followers have been keen to tweet us pictures of the #BJRTravelbug mascot in a variety of far flung locations. Pick yours up at our conference booth and let @BJR_Radiology know where it gets to. As the oldest scientific journal in the field of radiology and related sciences, BJR has published a number of pioneering articles, including the first description of computed tomography by Sir Godfrey Hounsfield in 1973.1 A valuable historical resource, the full BJR archive has been digitized and articles in the collection start just months after the discovery of X-rays in 1896. In addition we have recently launched a new open access, online only sister journal to BJR, BJR|case reports. We’ve been thrilled with the positive reception BJR|case reports has received so far and look forward to developing it into a key educational resource. BJR is a competitive, multidisciplinary, high quality journal with a flexible open access option and our articles are available quicker than ever before—after a paper is accepted for publication, it appears in its final version within only 3 weeks! We hope you will join our growing list of international authors, readers and reviewers by reading BJR articles, reviewing papers and submitting your work.

Reference 1.

Hounsfield GN. Computerized transverse axial scanning (tomography): Part I. Description of system. Br J Radiol 1973; 46: 1016–22. doi:10.1259/0007-1285-46-552-1016

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BJR Received: 8 June 2014

Accepted: 13 October 2014

doi: 10.1259/bjr.20140416

Cite this article as: Baldwin DR, O’Dowd EL. Next steps and barriers to implementing lung cancer screening with low-dose CT. Br J Radiol 2014;87:20140416.

COMMENTARY

Next steps and barriers to implementing lung cancer screening with low-dose CT 1

D R BALDWIN, MD, FRCP and 2E L O’DOWD, MB ChB, MRCP (UK)

Respiratory Medicine Unit, David Evans Research Centre, Nottingham University Hospitals, Nottingham, UK Division of Public Health and Epidemiology, University of Nottingham, Nottingham City Hospital, Nottingham, UK

Address correspondence to: Professor David R Baldwin E-mail: david.baldwin@nuh.nhs.uk

The mortality from lung cancer exceeds that from breast, colorectal and pancreatic cancer combined. This is because three-quarters of patients present with late-stage disease when treatment is palliative and survival is short. If detected early, lung cancer can be cured, so screening would seem to be an important intervention. Until the publication of the National Lung Screening Trial (NLST),1 there was no evidence to support the implementation of screening with lowdose CT (LDCT). This publication has sparked a different approach to the subject from asking whether it works to what we still need to know to implement with the least harm and cost. These remaining issues will be reviewed. DOES LUNG CANCER MERIT A SCREENING PROGRAMME? Criteria for effective screening programmes have been defined in the USA and UK.2,3 The UK Screening Committee has 23 criteria for an effective national screening programme.3 The first is that the disease should be an important health problem—the annual mortality from lung cancer is 35,000 in the UK and almost 160,000 in the USA, more than that for breast, colorectal and pancreatic cancer combined.4,5 Other criteria sensibly include that the problem exists despite the delivery of optimal prevention, treatment and the consideration of new treatments. Smoking cessation interventions have had a major impact on mortality from lung cancer,6 but despite continued efforts, the rate of reduction of smoking is slowing and there remain many ex-smokers at risk. Three-quarters of patients present with late-stage disease and the treatment at this stage has had little impact on mortality despite significant advances in targeted therapy. There is some evidence that radical treatment rates are increasing, but at only a modest rate and mainly in the older age group.7 Other important criteria are that there should be welldefined risk factors for the disease and a validated, sensitive and acceptable screening test that can be applied effectively to reduce mortality. Until recently, the latter criterion had not been met. Thus, lung cancer is a health problem that clearly meets these disease-specific criteria.

THE EVIDENCE FOR LUNG CANCER SCREENING Many of the early trials of screening with chest radiographs, sputum cytology and later CT were not designed to minimize the now well-established biases operating in screening trials that result in longer survival but no reduction in mortality.8 Overdiagnosis is a bias that results from cancers being diagnosed that would never limit life expectancy, but once diagnosed by screening improves the overall results of the screening arm in a trial against no screening or a less sensitive screening method. Lead time bias is where, as a result of screening, cancer is diagnosed earlier, and this results in a longer measured survival, even though there is no effect on the eventual date of death. Lagtime bias is the tendency of more indolent tumours to be detected by screening because of their long pre-symptomatic phase, whilst the very aggressive ones tend to present between the screens, so present equally in the screened and control arms. What was needed was a well-designed, adequately powered randomized trial. The US-based NLST1 randomized 53,454 people aged between 55 and 74 years, who had smoked within 15 years and accumulated a minimum of 30 pack years, to 3 annual screens with either LDCT or chest radiography. The trial recruited between 2002 and 2004, and in October 2010 it was stopped 1 year earlier than planned as the pre-specified lung cancer mortality reduction of 20% had been reached in the LDCT arm. The trial also showed a reduction in all-cause mortality of 6.7%. The number needed to screen (NNS) to prevent 1 lung cancer death was 320 for those who completed at least 1 screen. In the breast mammography trials, for females aged 50–59 years, the NNS was 1139 after 11–20 years follow-up; the NNS for flexible sigmoidoscopy was 817 to prevent 1 colon cancer death.9,10 Other much smaller trials of moderate or low quality have reported on early mortality but none has the statistical power to show a difference, and when combined with the results of NLST in a meta-analysis, there was still a 19% reduction in lung cancer-specific mortality.11,12 Thus, the criteria for a validated and sensitive screening test had finally been met.

BJR

DR Baldwin and EL O’Dowd

Table 1. Barriers to lung cancer screening implementation and proposed solutions

Key problem

What is the barrier to implementation?

What is the solution?

1. NNS

• Higher false-positive rates and decreased cost effectiveness if the inclusion criteria are too broad

• Use of risk prediction models rather than just age and smoking cut-offs to better guide who should be screened (UKLS)

2. Radiation exposure

• Estimates suggest 1 radiation-induced lung cancer for every 22 lung cancer deaths prevented • Positron emission tomography-CT in the investigation of false-positive lesions increases radiation dose

• Low-dose CT reduces radiation dose to around one-ﬁfth of conventional CT • Clear selection criteria for screening and robust nodule management guidelines will reduce false positives

3. False-positive scans

• In NLST, there were around 25 benign lesions for every cancer detected, with psychological and possible physical harm from further investigations

• Volumetric nodule assessment employed by NELSON and UKLS to better assess nodules and reduce false positives • Risk assessment models to guide who should be screened

4. Overdiagnosis

• Estimates suggest 10–20% overdiagnosis with screening again with associated physical and psychological harm

• Clear nodule guidelines, with a cautious approach to subsolid nodules (more likely to represent more indolent tumours)

• Concern regarding false reassurance with screening leading to continued/new uptake of smoking

• Combination of screening with smoking cessation programmes • Somewhat reassuring smoking cessation results from NLST (but substantially higher smoking cessation in both arms than in background rates)

6. Cost effectiveness

• Some models based on NLST are too expensive

• Careful and clear guidance regarding management of positive/indeterminate CT results • Risk proﬁling of the screened population to reduce the NNS • Multiple health interventions including smoking cessation

7. Hard-to-access groups

• Work suggests that those at highest risk of developing lung cancer are least likely to participate in/complete screening programmes, with consequent cost effectiveness implications

• Research is ongoing to determine how best to engage and retain these high-risk and hard-to-access groups

5. Smoking cessation

NLST, National Lung Screening Trial; NNS, number needed to screen; UKLS, United Kingdom Lung Screen.

During 2011 and 2012, several US professional organizations made recommendations for implementation of screening in people who would have met the NLST entry criteria, with some extensions. Finally, the US Preventive Services Task Force (USPST), following a commissioned independent analysis of the evidence, recommended that lung cancer screening should be offered according to NLST entry criteria but with an extension of the upper age limit to 80 years.11 More recently, the Centers for Medicare and Medicaid national coverage determination panel were not convinced that the beneﬁts of CT screening outweighed the harms and rated the intervention at 2.2 out of 5.0. This was thought especially true in the older age group where there is a higher false-positive rate. However, Pinsky et al13 have shown that people aged 65–75 years beneﬁt as much as those aged under 65 years as their higher prevalence of lung cancer offsets the harms from the greater number of false positives. Outside the USA, there have been international consensus statements that have made recommendations for further research and analysis of the existing randomized trials in Europe.14,15 The Dutch–Belgium NELSON trial16 is due to report on mortality in 2015–16, and results of all of the European trials may be pooled around the same time. These data will answer important questions

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about how better nodule management and more sophisticated radiology inﬂuences the efﬁcacy of screening. There is considerable debate about whether the results of NELSON should be awaited before screening programmes are implemented. THE REMAINING ISSUES AND POTENTIAL BARRIERS TO IMPLEMENTATION So what are the remaining questions and potential barriers to implementation of LDCT screening in the UK? The answer relates to important remaining questions about selection, recruitment, the level of harm, optimal clinical pathways and cost effectiveness, all of which are criteria set by the UK National Screening Committee (Table 1). The recommendations made by the USPST may have gone too far, not by extending screening to the older age group, but by including younger people without a more sophisticated estimate of the risk of lung cancer. More recent publications have suggested that by better selection using a risk prediction model, there might have been more lives saved with reduction in the NNS to 270.17 If screening were to have been restricted to the subjects with a .1.25% risk of lung cancer death over 5 years, this falls further to 166.18 Better selection methods are available and validated, and their use may go some way to placate the recently expressed reservations about CT screening from Medicare and Medicaid.

Br J Radiol;87:20140416

Commentary: implementing lung cancer screening with low-dose CT

BJR

Figure 1. United Kingdom Lung Screen nodule care pathway management protocol. diam, diameter; dmax, maximum diameter; dmean, mean diameter; dmin, minimum diameter; max, maximum; MDCT, multidetector CT; MDT, multidisciplinary team; VDT, volume doubling time.

One key remaining issue is recruitment of people into screening programmes. Lung cancer is much more common in less economically advantaged groups, who also represent a hard-toaccess group. NLST recruited patients who were better educated and more afﬂuent than the US census average1 and United Kingdom Lung Screen (UKLS) noted that the lower socioeconomic groups were less likely to participate despite being at higher overall risk.19 The answer to this issue is not known; it is a topic of ongoing research projects and will be an important factor to monitor during implementation. Physical harm may result from radiation and further investigation of abnormal ﬁndings, and psychological harm may result from the resulting anxiety. LDCT reduces the radiation

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dose to approximately one-fifth of a typical thoracic CT, and this equates to less than half a person’s annual background radiation dose. Based on modelling, the USPST estimated that annual CT screening for lung cancer would cause 1 radiation-induced lung cancer death for every 22 prevented lung cancer deaths.11 Further improvements in technology may improve this figure. CT detects many benign nodules and masses (about 25 for every cancer detected). In the NLST, 59/26,722 (0.2%) of participants underwent a CT-guided lung biopsy for a benign lesion and 7 (0.03%) had a major complication.1 Clinical management pathways were not pre-specified in NLST, and they found that, where data were available, 2.2% of participants underwent positron emission tomography thus receiving a much higher radiation

Br J Radiol;87:20140416

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DR Baldwin and EL O’Dowd

dose. The Dutch–Belgian NELSON trial and the UKLS pilot trial both employ LDCT follow-up by using volume measurements rather than diameter to detect growth.16,20 This reduces the number of false-positive screens and defines more accurately the need for invasive procedures. Optimal screening follow-up pathways are becoming clear and will limit false-positive tests and the harm from further investigation. The nodule management algorithm for UKLS is shown in Figure 1. People who are overdiagnosed do not benefit from early diagnosis but are subject to the same harm as others from investigations, treatment and the psychological impact of being told they have cancer. They may, however, benefit from health interventions that are provided with screening such as smoking cessation advice. Estimates based on the excess observed in NLST and in lead time estimation from a variety of sources suggest that 10–20% of screen-detected cancers are overdiagnosed (a maximum 18.5% in NLST).21,22 Thus, the number of cases overdiagnosed is similar to the number of lives saved; this is similar to estimates for breast cancer screening, where recent reviews suggest between 0.5 and 3.0 overdiagnosed cases per life saved.23,24 However, overdiagnosis is far more likely where the final diagnosis was bronchoalveolar cell carcinoma (now lepidic predominant pattern adenocarcinoma). Thus, a cautious approach to subsolid nodules found during screening may limit the harm from overdiagnosis. Psychological harm has been shown to be minimal in screening trials with a transient increase in anxiety and distress in subjects with positive or indeterminate findings, returning to baseline after the second screen.25 Distress and fear of cancer decreased in subjects with negative results compared with those at baseline. Whether people might be falsely reassured and continue or even start smoking is not known; smoking cessation rates were 14.5% in the LDCT arm compared with 19.1% in the control arm; both of these were higher than the 6–7% background rate.26 The cost effectiveness of a programme will be strongly influenced by the frequency of screening, duration of screening programme, risk profile of the screened population, uptake of screening in hard-to-reach groups and smoking cessation. The range of reported incremental cost effectiveness ratios (ICERs) remains considerable. A US simulation of the annual screening of ever-smokers using national epidemiological and Mayo Clinic CT trial data estimated the ICERs to be $110,000–$160,000 per

quality-adjusted life year (QALY) gained. A US stage-shift model using the Early Lung Cancer Action Program (ELCAP) protocols and outcomes data, Medicare tariffs and national survival rates by stage-produced ICER estimates ,$19,000.27 The model was re-estimated for annual screening and yielded baseline estimates of $28,000 or $47,000 depending on whether the model’s cancer stage predictions derived from the ELCAP- or the NLSTreported stage shift;28 costs fell further with smoking cessation to $16,000 or $23,000, respectively. The lowest ICER estimated is around $1464 per QALY gained, reported for Israel.29 A POTENTIAL WAY FORWARD Since the publication of NLST, there has been much international discussion about the issues outlined here and recommendations made for further work to be performed to support implementation.14,15 The USA has gone the furthest in recommending national implementation of screening, and work is ongoing to answer important remaining questions. The solution will vary according to the individual country’s healthcare system and may increase the work of radiologists and radiographers. The efficient use of nodule management algorithms and trained non-radiologist readers in combination with computeraided detection software may mitigate this.12 Private healthcare providers are offering CT screening in many countries and the concern is that this is not regulated. The importance of adherence to standards that serve to minimize harm and maximize benefit has been emphasized.30 The Committee on Medical Aspects of Radiation Exposure will publish a report in 2014 further emphasizing the need for an expert approach in the independent sector.31 However, the most important concern with private provision of screening is that it does nothing for the majority of those at risk, as lung cancer is more common in the less advantaged. Those of us who care for patients with lung cancer want screening to be introduced as soon as possible for all those at risk, but it has to be on the basis that it is cost effective because of the high total cost. To ensure effective implementation, it may be best to start with a programme that targets those most at risk and employs pathways that minimize risk of harm, including those due to overdiagnosis, and then expand as the essential unanswered issues are clarified. A biennial or annual screen from the age of 60 years in those with a risk of lung cancer in excess of 1% per annum, with clear protocols for the management of abnormal findings would fit, with ongoing research into the best methods for selection and recruitment.12

REFERENCES 1.

National Lung Screening Trial Research Team; Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409. doi: 10.1056/ NEJMoa1102873 Available from: http://www.cancer.gov/ cancertopics/pdq/screening/overview/ HealthProfessional#Section_10

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UK National Screening Committee. Programme appraisal criteria. Available from: http://www.screening.nhs.uk/ criteria Cancer Research UK. Cancer mortality in the UK in 2012. Available from: http://publications. cancerresearchuk.org/downloads/Product/ CS_REPORT_MORTALITY.pdf America Cancer Society. Cancer facts and ﬁgures 2014. Available from: http://www.

cancer.org/acs/groups/content/@research/ documents/webcontent/acspc-042151.pdf Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two casecontrol studies. BMJ 2000; 321: 323–9. Riaz SP, Linklater KM, Page R, Peake MD, Møller H, L¨uchtenborg M. Recent trends in resection rates among non-small cell lung

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Commentary: implementing lung cancer screening with low-dose CT

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cancer patients in England. Thorax 2012; 67: 811–14. doi: 10.1136/thoraxjnl-2012-201768 Black WC. Computed tomography screening for lung cancer: review of screening principles and update on current status. Cancer 2007; 110: 2370–84. Humphrey LL, Helfand M, Chan BK, Woolf SH. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 137: 347–60. Schoen RE, Pinsky PF, Weissfeld JL, Yokochi LA, Church T, Laiyemo AO, et al. Colorectalcancer incidence and mortality with screening ﬂexible sigmoidoscopy. N Engl J Med 2012; 366: 2345–57. doi: 10.1056/ NEJMoa1114635 Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation. Ann Intern Med 2013; 159: 411–20. doi: 10.7326/0003-4819-159-6201309170-00690 Field JK, Hansell DM, Duffy SW, Baldwin DR. CT screening for lung cancer: countdown to implementation. Lancet Oncol 2013; 14: e591–600. doi: 10.1016/S1470-2045(13)70293-6 Pinsky PF, Gierada DS, Hocking W, Patz EF Jr, Kramer BS. National Lung Screening Trial ﬁndings by age: medicare-eligible versus under-65 population. Ann Intern Med Sep 2014. doi: 10.7326/M14-1484 Field JK, Aberle DR, Altorki N, Baldwin DR, Dresler C, Duffy SW, et al. The International Association Study Lung Cancer (IASLC) Strategic Screening Advisory Committee (SSAC) response to the USPSTF recommendations. J Thorac Oncol 2014; 9: 141–3. doi: 10.1097/JTO.0000000000000060 Field JK, Smith RA, Aberle DR, Oudkerk M, Baldwin DR, Yankelevitz D, et al. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report. J Thorac Oncol 2012; 7: 10–19. doi: 10.1097/JTO.0b013e31823c58ab van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R,

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et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009; 361: 2221–9. doi: 10.1056/ NEJMoa0906085 Tammemägi MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013; 368: 728–36. doi: 10.1056/NEJMoa1211776 Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013; 369: 245–54. doi: 10.1056/ NEJMoa1301851 McRonald FE, Yadegarfar G, Baldwin DR, Devaraj A, Brain KE, Eisen T, et al. The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening. Cancer Prev Res (Phila) 2014; 7: 362–71. doi: 10.1158/ 1940-6207 Baldwin DR, Duffy SW, Wald NJ, Page R, Hansell DM, Field JK. UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer. Thorax 2011; 66: 308–13. doi: 10.1136/thx.2010.152066 Independent UKPoBCS. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380: 1778–86. doi: 10.1016/S0140-6736(12) 61611-0 Duffy SW, Field JK, Allgood PC, Seigneurin A. Translation of research results to simple estimates of the likely effect of a lung cancer screening programme in the United Kingdom. Br J Cancer 2014; 110: 1834–40. doi: 10.1038/bjc.2014.63 Patz EF Jr, Pinsky P, Gatsonis C, Sicks JD, Kramer BS, Tammemägi MC, et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med 2014; 174: 269–74. doi: 10.1001/ jamainternmed.2013.12738 Puliti D, Duffy SW, Miccinesi G, de Koning H, Lynge E, Zappa M, et al. Overdiagnosis in

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mammographic screening for breast cancer in Europe: a literature review. J Med Screen 2012; 19 (Suppl. 1): 42–56. van den Bergh KA, Essink-Bot ML, Borsboom GJ, Scholten ET, van Klaveren RJ, de Koning HJ. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J 2011; 38: 154–61. doi: 10.1183/09031936.00123410 van der Aalst CM, van den Bergh KA, Willemsen MC, de Koning HJ, van Klaveren RJ. Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch–Belgian randomised controlled lung cancer screening trial. Thorax 2010; 65: 600–5. doi: 10.1136/thx.2009.133751 Pyenson BS, Sander MS, Jiang Y, Kahn H, Mulshine JL. An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost. Health Aff (Millwood) 2012; 31: 770–9. doi: 10.1377/hlthaff.2011.0814 Villanti AC, Jiang Y, Abrams DB, Pyenson BS. A cost–utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLoS One 2013; 8: e71379. doi: 10.1371/journal. pone.0071379 Shmueli A, Fraifeld S, Peretz T, Gutfeld O, Gips M, Sosna J, et al. Cost-effectiveness of baseline low-dose computed tomography screening for lung cancer: the Israeli experience. Value Health 2013; 16: 922–31. doi: 10.1016/j.jval.2013.05.007 Field JK, Baldwin D, Brain K, Devaraj A, Eisen T, Duffy SW, et al. CT screening for lung cancer in the UK: position statement by UKLS investigators following the NLST report. Thorax 2011; 66: 736–7. doi: 10.1136/ thoraxjnl-2011-200351 Department of Heath. Justification of computed tomography (CT) for individual health assessment. Expert Working Party Report. Available from: https://www. gov.uk/government/uploads/system/ uploads/attachment_data/file/326572/ IHA_-_June_Report.pdf

Br J Radiol;87:20140416

BJR Received: 7 October 2013

doi: 10.1259/bjr.20130629 Revised: 4 November 2013

Accepted: 4 November 2013

© 2014 The Authors. Published by the British Institute of Radiology under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial reuse, provided the original author and source are credited.

Cite this article as: Brenner DJ. What we know and what we don’t know about cancer risks associated with radiation doses from radiological imaging. Br J Radiol 2014;87:20130629.

RADIOBIOLOGY SPECIAL FEATURE: COMMENTARY

What we know and what we don’t know about cancer risks associated with radiation doses from radiological imaging D J BRENNER, PhD, DSc Center for Radiological Research, Columbia University Medical Center, New York, NY, USA Address correspondence to: Professor David J. Brenner E-mail: djb3@columbia.edu

ABSTRACT Quantifying radiation-induced cancer risks associated with radiological examinations is not easy, which has resulted in much controversy. We can clarify the situation by distinguishing between higher dose examinations, such as CT, positron emission tomography–CT or fluoroscopically guided interventions, and lower dose “conventional” X-ray examinations. For higher dose examinations, the epidemiological data, from atomic bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks: in summary, very small but unlikely to be zero. For lower dose examinations, we have very little data, and the situation is much less certain, however, the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective.

The debates about the cancer risks associated with very low-dose radiation exposures will surely not end soon. Even if we really could quantitate the risks (or lack of risks) associated with some very low radiation doses, we would immediately start to wonder about the risks associated with further lower doses. We will focus here on what we know (and what we do not know) about the cancer risks associated with doses from radiological imaging. Almost all radiological doses are “small”, in the context of, for example, radiotherapeutic doses; however, one can clearly distinguish between low radiological doses associated with many conventional examinations such as dental or chest examinations (organ doses typically ,0.5 mGy) and higher radiological doses associated with CT, positron emission tomography (PET)-CT or ﬂuoroscopically guided complex interventions (organ doses for a single examination or series of examinations typically between 5 and 100 mGy). As we shall discuss, this divide in dose ranges corresponds quite well to the dose range where we do know a good deal about radiation risks (5–100 mGy) and the dose range (,1 mGy) where we know far less. We shall discuss brieﬂy what we know and do not know in both these radiation dose ranges, but it is important to view these considerations in the context of the potential

benefits associated with the corresponding imaging procedure.1 When a radiological examination of any sort is clinically justified, its benefits will almost always far outweigh any radiation risks. That being said, we still need to optimize radiological examinations (use the lowest dose consistent with obtaining the required information) and to justify radiological examinations (minimize clinically unnecessary procedures); however, the significance of such optimization and justification depends entirely on the magnitude (if any) of the associated radiation risks. 1–3 WHAT IS KNOWN AT HIGHER RADIOLOGICAL DOSES In the organ dose range from 5 to 100 mSv, the evidence that cancer risk is slightly increased is now reasonably strong, although certainly not definitive. As always, we first turn to the atomic bomb (A-bomb) survivors because the numbers are large and the follow-up is long. A common comment about the A-bomb survivors is that it is a high-dose cohort and, therefore, one needs to extrapolate the risks to radiologically relevant doses. In fact, there are about 28 000 individuals in the well-studied Life Span Study (LSS) cohort, whose dose estimates are in the 5–100 mSv range, which is .60% of the total exposed cohort.4 Focusing only on the cohort members exposed to low doses,4 there is a statistically significant (p 5 0.01) dose response for solid cancer incidence (compared with controls) when the analysis is restricted to LSS cohort members who received doses of

Commentary: Cancer risks associated with radiation doses from radiological imaging

#150 mSv, and a marginally significant dose response (p 5 0.08) when the analysis was restricted to doses of #100 mSv. Similar results are seen for cancer mortality.5 One important conclusion to draw from these p-values is that epidemiological studies on populations exposed to further lower doses (with presumably correspondingly lower risks) are unlikely to have enough significance to draw quantitative conclusions. Thus, for example, despite the large number of individuals studied (approximately 400 000), the major international epidemiological study of radiation workers exposed at low-dose rates to an average dose of 20 mGy has given quite equivocal results, consistent with zero risk and also consistent with risks derived from A-bomb survivors.6 In retrospect, this is not so surprising. One approach to epidemiological assessment of risks at lower doses is to focus on scenarios where the signal-to-background ratio is likely to be higher than is the case overall. One example is the study of childhood cancers after in utero diagnostic imaging. Here, the absolute risk (the signal) is expected to be high because the subjects were exposed in utero, and the background is expected to be low because childhood cancers are rare, and, indeed, the Oxford Study of Childhood Cancers was able to detect a significant increase in paediatric cancer risk for a mean dose of only 6 mGy.7 The same logic, of tailoring the epidemiological study to improve the signal-to-background ratio, applies to two recently published epidemiological studies of cancer risks associated with paediatric exposure to CT scans, both with a relatively short mean follow-up of about 10 years.8,9 The relatively short follow-up after paediatric exposure allows radiation-induced cancers with short latency to be detected while limiting the background from cancers appearing in the “cancer-prone” years of late middle age. Both studies were very large and showed a statistically significant association between the number of CT scans and the increased cancer risk. For example, as illustrated in Figure 1, the second paediatric CT study9 reported a significant dose–response relation over the range from zero to more than three CT scans, with an increase in the cancer incidence rate ratio, relative to controls, of 0.16 (95% confidence interval: 0.13–0.19) for each additional CT scan. Two caveats are important for these epidemiological studies of radiation risks associated with CT scans. The first is the possibility that the reason for a paediatric CT might also be the cause of subsequent cancer; for example, an undiagnosed brain tumour might have been the cause of symptoms for which the patient had a CT scan; a head trauma might have been the reason for a CT scan, but perhaps might itself be linked to increased cancer risks; or epilepsy might have been the cause of symptoms that prompted the CT scan and might be linked with increased cancer risks. Broadly termed “reverse causality”,10 in the CT context, these issues relate primarily to brain tumours after head CT scans, with fewer possible such scenarios for leukaemia. So, it is important to understand whether these risks remain if brain tumours after head CT scans are removed from the analyses; in fact, the relative risks stay much the same,9 so it seems unlikely that reverse causality is a major effect.

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Figure 1. Cancer incidence rate ratios for all cancers in individuals who received CT scans vs those who did not. The right most data point refers to$3 CT scans, with the mean number of CT scans being 3.5. The data shown here are for a lag period (exclusion period before cancer diagnosis) of 1 year; similar results were reported9 for lag periods of 5 or 10 years. Reproduced with permission from BMJ Publishing Group and originally published in9. CI, confidence interval.

A second caveat relates to the fact that radiation-induced latency periods can be many decades;4 because the paediatric CT studies8,9 have fairly short follow-up times (of the order of 10 years), they cannot directly estimate lifetime cancer risks; rather, they provide only a snapshot of the overall risk. However, when corrected for follow-up, CT risks previously estimated from Abomb survivors are, in fact, quite similar to the epidemiological results.11 So, the paediatric CT risk estimates do provide some validation that we have a reasonable understanding of the overall cancer risks associated with CT and PET/CT exposures: in short, very small individual risks but unlikely to be zero. WHAT IS KNOWN AT LOWER RADIOLOGICAL DOSES At organ doses ,1 mGy, typical of “conventional” radiological examinations, the short answer is that we have little or no reliable data. The natural background cancer risk in humans of .40% is too large for a realistic reasonably powered epidemiological study when the expected risks are, at most, much less than 0.1%. These same considerations apply to laboratory animal studies, where even when using mice with very low background cancer rates, radiation-induced cancer studies at these doses are not feasible.12 A further problem is the absence of credible in vitro models for radiation-induced cancer: although many low-dose studies have been reported using genomic changes, including changes in gene expression, DNA strand breaks, mutations or chromosome aberrations, there is no convincing quantitative/ mechanistic connection between any of these end points and radiation-induced cancer, which is of course a much later end point.13 Perhaps, the most plausible in vitro model for radiationinduced cancer is in vitro oncogenic transformation, but, even for this, end point studies at doses #1 mGy are not feasible.14,15 The absence of data at these low doses is unfortunate and inevitably leads to uncertainty and controversy. As an example, three studies16–18 of historical mortality risks in radiologists concluded that there was a statistically signiﬁcant increase in

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D J Brenner

risk,16 a statistically significant decrease in risk,17 or that there was no significance difference compared with other physicians.18 This diversity is not surprising given the limited power of such studies, and interpretation of all results at very low doses, whether in vitro or in vivo, should be undertaken with much caution. From the radiological perspective, however, the collective dose from lower dose examinations is comparatively unimportant compared with that from higher dose studies, such as CT or PET-CT.19 However, these issues are extremely important in other contexts, such as understanding the public health significance of the exposures at Chernobyl and Fukushima. CONCLUSION Quantifying radiation-induced cancer risks associated with radiological examinations is not easy. For higher dose examinations, the epidemiological data, from A-bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks; in summary, very small but unlikely to be zero. For lower dose

examinations, we have very little data and the situation is much less certain, but the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective. Historically, the radiation doses for which we have quantitative information about cancer risks have steadily decreased with time. Around 1980, for example, almost nothing was known about cancer risks associated with a 100 mGy dose.20 This has clearly changed in the past 30 years. We have probably reached a limit in terms of what can be done using classical epidemiological techniques, and the future must surely lie in augmenting epidemiology with radiobiological concepts.21 As one obvious example, if a deﬁnitive “ﬁngerprint” of a radiation-induced tumour could be found, many of the issues associated with our high-background cancer rate would disappear, and epidemiological studies at lower doses would become more feasible. FUNDING This work was supported by NIH grants U19 A1067773 and P41 EB002033.

REFERENCES 1.

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Hricak H, Brenner DJ, Adelstein SJ, Frush DP, Hall EJ, Howell RW, et al. Managing radiation use in medical imaging: a multifaceted challenge. Radiology 2011; 258: 889–905. doi: 10.1148/radiol.10101157 Brenner DJ, Hricak H. Radiation exposure from medical imaging: time to regulate? JAMA 2010; 304: 208–9. doi: 10.1001/jama.2010.973 European Society of Radiology: White paper on radiation protection by the European Society of Radiology. Insight Imaging 2011; 2: 357–62. doi: 10.1007/s13244-011-0108-1 Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, et al. Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat Res 2007; 168: 1–64. doi: 10.1667/RR0763.1 Preston DL. From epidemiology to risk factors. Proceeding of the Third MELODI Workshop; November 2–4 2011; Rome, Italy. Available from: www.melodi-online.eu/doc/ preston.pdf. Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, et al. The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: estimates of radiation-related cancer risks. Radiat Res 2007; 167: 396–416. doi: 10.1667/ RR0553.1 Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol 1997; 70: 130–9. Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours:

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a retrospective cohort study. Lancet 2012; 380: 499–505. doi: 10.1016/S0140-6736(12) 60815-0 doi: 10.1016/S0140-6736(12)60815-0 Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen SK, Byrnes GB, et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 346: f2360. doi: 10.1136/bmj.f2360 NCRP. Uncertainties in the estimation of radiation risks and probability of disease causation. Bethesda, MD: National Council on Radiation Protection and Measurements; 2012. Brenner DJ, Hall EJ. Cancer risks from CT scans: now we have data, what next? Radiology 2012; 265: 330–1. doi: 10.1148/ radiol.12121248 Ullrich RL, Storer JB. Inﬂuence of gamma irradiation on the development of neoplastic disease in mice. I. Reticular tissue tumors. Radiat Res 1979; 80: 303–16. Goodhead DT. Fifth Warren K. Sinclair keynote address: issues in quantifying the effects of low-level radiation. Health Phys 2009; 97: 394–406. doi: 10.1097/ HP.0b013e3181ae8acf Borek C, Hall EJ, Zaider M. X rays may be twice as potent as gamma rays for malignant transformation at low doses. Nature 1983; 301: 156–8. Mill AJ, Frankenberg D, Bettega D, Hieber L, Saran A, Allen LA, et al. Transformation of C3H

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10T1/2 cells by low doses of ionising radiation: a collaborative study by six European laboratories strongly supporting a linear dose-response relationship. J Radiol Prot 1998; 18: 79–100. Matanoski GM, Seltser R, Sartwell PE, Diamond EL, Elliott EA. The current mortality rates of radiologists and other physician specialists: deaths from all causes and from cancer. Am J Epidemiol 1975; 101: 188–98. Berrington A, Darby SC, Weiss HA, Doll R. 100 years of observation on British radiologists: mortality from cancer and other causes 1897-1997. Br J Radiol 2001; 74: 507–19. Carpenter LM, Swerdlow AJ, Fear NT. Mortality of doctors in different specialties: ﬁndings from a cohort of 20000 NHS hospital consultants. Occup Environ Med 1997; 54: 388–95. Mettler FA Jr, Bhargavan M, Faulkner K, Gilley DB, Gray JE, Ibbott GS, et al. Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources— 1950-2007. Radiology 2009; 253: 520–31. doi: 10.1148/radiol.2532082010 NRC. The effects on populations of exposure to low levels of ionizing radiation: BEIR III. Washington, DC: National Academy Press; 1980. Preston RJ, Boice JD Jr, Brill AB, Chakraborty R, Conolly R, Hoffman FO, et al. Uncertainties in estimating health risks associated with exposure to ionising radiation. J Radiol Prot 2013; 33: 573–88. doi: 10.1088/0952-4746/33/3/ 573

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BJR Received: 18 October 2013

Accepted: 10 December 2013

doi: 10.1259/bjr.20130662

Cite this article as: Morgan B, Adlam D, Robinson C, Pakkal M, Rutty GN. Adult post-mortem imaging in traumatic and cardiorespiratory death and its relation to clinical radiological imaging. Br J Radiol 2014;87:20130662.

FORENSIC RADIOLOGY SPECIAL FEATURE: REVIEW ARTICLE

Adult post-mortem imaging in traumatic and cardiorespiratory death and its relation to clinical radiological imaging 1

B MORGAN, PhD, FRCR, 2D ADLAM, DPhil, MRCP, 1C ROBINSON, MSc, 1M PAKKAL, MBBS, FRCR and 3G N RUTTY, MD, FRCPath

Imaging Department, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, UK Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK 3 East Midlands Forensic Pathology Unit, University of Leicester, Leicester, UK 2

Address correspondence to: Professor Bruno Morgan E-mail: bm11@leicester.ac.uk

ABSTRACT The use of post-mortem imaging is expanding throughout the world with increasing use of advanced imaging techniques, such as contrast-enhanced CT and MRI. The questions asked of post-mortem imaging are complex and can be very different, for example for natural sudden death investigation will focus on the cause, whereas for trauma the cause of death is often clear, but injury patterns may be very revealing in investigating the background to the incident. Postmortem imaging is different to clinical imaging regarding both the appearance of pathology and the information required, but there is much to learn from many years of clinical research in the use of these techniques. Furthermore, it is possible that post-mortem imaging research could be used not only for investigating the cause of death but also as a model to conduct clinically relevant research. This article reviews challenges to the development of post-mortem imaging for trauma, identification and cardiorespiratory death, and how they may be influenced by current clinical thinking and practice.

Generally, post-mortem investigation is carried out to ascertain four basic principles of who the deceased was, where they died, when they died and by what means (why) they came to their death. Imaging is normally only pertinent to the “whom” and “why” they died, and the emphasis on these questions may be completely different; for example a case of a witnessed natural death at home compared with a massfatality traumatic incident. A consistent theme, however, is that investigation should be carried out quickly and efﬁciently, for the sake of both the family and legal services. Imaging in post-mortem investigation is as old as radiography (X-rays) itself, but there has recently been a massive expansion in the use of imaging techniques to assist or supplant traditional autopsy techniques in post-mortem investigation. Whilst there are few who doubt the ability of post-mortem CT (PMCT)1 to demonstrate fractures, foreign bodies and major haemorrhagic injuries,2 there have been many false dawns in this ﬁeld. What is clear is that an “unenhanced” PMCT scan can only go so far in the investigation of death,3–5 and the emphasis is now moving from non-invasive techniques to minimally invasive techniques, “enhancing” the scan.6,7

Similar to development in the clinical world, many new imaging techniques struggle to live up to their hype.8 However, by incremental progress, imaging has transformed clinical management in the living, and it is also likely to do so in the investigation of the cause of death. This article looks into a few areas where research is ongoing to develop these techniques. The article concentrates on three main themes: the role of imaging in traumatic death, specifically relating to mass fatalities and disaster victim identification; the lessons that can be learnt from clinical imaging practice to inform the investigation of cardiovascular death; and, finally, the importance of other techniques being introduced, such as ventilation scans, dual source CT and MRI techniques. TRAUMATIC DEATH AND IDENTIFICATION Radiography is particularly useful in traumatic or suspicious deaths, and for many years this has proved satisfactory to aid identification (whom), particularly if accompanied by previous dental radiographs or dental records. Although DNA analysis and fingerprinting are preferred identification

Review article: Research directions for adult post-mortem imaging

strategies, forensic odontological/dental examination has many unique markers that may be compared with previous dental records or preferably radiographs. The other radiographic imaging is classified as a secondary identifying system but is recognized and may be necessary if dental assessment is not possible. These tests are particularly useful in a “closed” situation where the task is identification of bodies from a known list of victims (e.g. from a passenger manifest). This approach exploits the principle that many people have unique pre-existing injuries that may be visible to a plain radiograph, such as a fracture. This is particularly useful when radiographs can be compared with those taken in life, such as those used by Singleton9 who managed to identify 24 of the 119 victims of SS Noronic fire disaster in 1949 by the sole use of radiology. However, with standard radiography, this can be a big task, such as for the Oklahoma City bombing response,10 which used 60 radiographers and 10 radiologists over a 10-day period to do full skeletal surveys, giving 6 positive identifications where other techniques were inconclusive. PMCT can offer all this from a single scan giving multiple potential identification options, including odontology,11 medical implants, fractures and sinuses,12 with new approaches still being identified. Although previous radiographs are more likely to be available than CT, PMCT images can be compared with previous radiographs using image manipulation.13,14 PMCT has a further advantage over plain radiographs in the assessment of soft tissues. This can be useful for detecting visceral abnormalities, particularly those resulting from surgery such as cholecystectomy, which would not be detectable on standard radiography and could be used to identify a body. Identification is much more difficult in an “open” disaster resulting in the death of unknown individuals or where there are no prior data or records available for comparison. In this situation, basic anthropological data are the starting point to establish the age and gender, and sometimes help in identifying the ethnicity of the victim. Standard anthropological examination often depends on osteology, which may require defleshing of bones, which is time consuming, destructive and against many religious and cultural beliefs.15 PMCT three-dimensional (3D) reconstructions are particularly useful in the assessment of bone architecture and are reliable for anthropological assessments, and potentially answer most anthropological questions without the need to strip bones.15–17 PMCT may also be useful in reuniting body parts in mass traumatic mortality.18 Radiography and fluoroscopy also help with the “by what means” question by locating fractures and foreign bodies, including bullets.2 In many cases, the cause of death is all too obvious in trauma. However, patterns of injury may be important to reconstruct details of how the traumatic death came about or to locate evidence. CT is very good in this aspect, as shown for road traffic collisions.19 PMCT has also proven to be useful in dealing with unlawful death, such as reconstructing bullet or stab wound trajectories.20–23 PMCT also has potential in the speed and efficiency of examination. Replacing traditional dental, fluoroscopic and standard

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X-ray equipment in a mass-fatality temporary mortuary could cut the examination time considerably and replace multiple radiation sources in a complex environment, improving radiation protection for staff.24 PMCT, as a single mobile machine, can be moved anywhere and run on a generator, while the data can be handled and sent anywhere in the world.25 PMCT does have disadvantages compared with radiography. Intraoral metal dental work can cause artefacts. These artefacts can be ameliorated to some extent with modern equipment using an extended CT scale or with post-processing. However, a very dense material such as dental mercury amalgam can cause irrecoverable artefact owing to photon depletion. Rigor mortis, or deformity due to exposure to severe heat, can delay scanning if displaced limbs cannot easily fit through the CT aperture. Soft tissue release can be performed in cases of burning.26 It is likely that PMCT will become the primary advanced imaging modality for traumatic death in adults.27 The PMCT and PM MRI (PMMR) balance is different in children for reasons relating to size and the types of relevant pathology suspected.28 However, new roles are being discovered for MRI, for example MRI spectroscopy of the brain, which has been shown to correlate to time from death.29 Other changes to the body that may occur after death, such as cooling, will also change the appearance of PMMR and need to be considered.30 PMMR also has a role in investigation of trauma, not only because of its superior soft tissue contrast resolution but also to assess bone fractures. Clinical scanning with MRI can detect marrow oedema in the absence of a radiologically visible fracture,31,32 and it is now being used in post-mortem investigation and can be useful to “date” fractures.33,34 MRI is also particularly appealing for the forensic examination of strangulation in the living, owing to its good soft tissue contrast resolution and lack of radiation exposure.35,36 The biggest challenges to the scientific community to provide a rapid and efficient service are firstly logistical and financial. Running a CT scanner is expensive in terms of both capital outlay and staff costs. Furthermore, until PMCT is more widely available, bodies have to be transported to a PMCT centre as part of their investigation. For mass fatalities, a mobile CT scanner can be taken almost anywhere, but having such an expensive resource continually available requires considerable planning. The second major task will be making sure that the evidence provided by imaging is believed. For example, plain film skeletal survey is a standard procedure for investigating sudden unexpected death in infancy,37 but it is easy to propose that PMCT could replace this entirely and add extra information.38 The principle of a radiographic skeletal survey to detect evidence of non-accidental injury predates the age of multidetector CT scanners.39–41 However, there is a lack of evidence to show that PMCT can do this, showing that the ability of PMCT to detect trauma to the bone, in general, is not enough, as specific injuries such as the characteristic “bucket handle” metaphyseal fractures must be confidently excluded.42 MRI may be sensitive to these metaphyseal fractures,31,43 and it is therefore unlikely that CT would be used in living patients owing to radiation exposure.

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This scenario demonstrates that all indications of PMCT in legal investigations should be clearly defined and should have their accuracy tested and validated by scientific review. Establishing the evidence for each indication and presenting it to the legal profession will become an important part of the ongoing research.44,45 CARDIOVASCULAR IMAGING The subject of vascular imaging and specifically coronary vascular imaging is discussed elsewhere in this issue (Grabherr S, Grimm J, Dominguez A, Vanhaebost J, Mangin P. Advances in post-mortem CT angiography. Br J Radiol 2014;87:20130488). However, this is a key issue, being the most common cause of sudden death in adults, and has relevance even if the specific cause of death is noncardiac, such as for a driver involved in a head-on road crash. Traditional autopsy and post-mortem imaging deliver a static view of tissue morphology, and previous studies have shown that luminal examination of the coronary arteries with PMCT angiography (PMCTA) can be equivalent to autopsy46–49 but highlight that PMCTA does not provide intraplaque pathology, such as plaque rupture or haemorrhage47 and cardiomyopathy.50 However, plaque rupture when present is often associated with other critically stenosed lesions. Also, sudden death from coronary artery disease can be difficult to diagnose with absolute certainty during autopsy if death is caused by immediate causes such as arrhythmia, even in the presence of stenosis or thrombus.51,52 Therefore, the cause of death is more commonly attributed to “ischaemic heart disease” on the “balance of probabilities”, if no other cause of death is ascertained,53,54 and pathologists often use an arbitrary 75% cut-off to define critical stenosis.55 This is demonstrably a flawed approach because, although the cause of death as shown in Figure 3a (introduced later) is clearly a ruptured abdominal aortic aneurysm, the degree of coronary artery disease in this case is more severe than in many cases of documented ischaemic heart disease death. One specific finding using targeted coronary PMCTA is that contrast injection under pressure can show luminal patency in regions of calcification where autopsy reports “critical stenosis”.47,56 The benefits of examining vessels under pressure during autopsy, and therefore mimicking normal physiological conditions, are well recognized but rarely performed in standard pathological practice.57

a stenosis.61,62 Recently, direct measurement of pressure changes across a stenosis has become possible using a “pressure wire” to measure the pressure gradient across a stenosis [fractional flow reserve (FFR)]. It has been shown that FFR is more predictive of clinical benefit from coronary artery stent than luminal narrowing alone, and only 80% of the 70–90% diameter stenoses are functionally significant.63 Treatment can therefore be targeted to functionally significant stenoses.64 These techniques can be translated into post-mortem investigation, particularly if the coronary arteries are examined under controlled pressure.56 It is possible to insert catheters into the coronary arteries in cadavers, including a “pressure wire” to measure intraluminal pressure and an optical coherence tomography (OCT) catheter to provide high-resolution “virtual histology” coronary images.65 Intravascular ultrasound could also be used. Catheter insertion is difficult in a minimally invasive manner similar to clinical practice, as there is no circulation to guide catheters into the arterial orifices and the shapes of the unpressurised vessels are different, so more work is required to perfect this (Figure 1). It is unlikely that these techniques will become routine, but they may contribute to a better understanding of coronary stenoses seen in post-mortem imaging. In clinical cardiology, FFR values may not directly correlate with maximal luminal narrowing, but they do correlate well with full 3D analysis of a stenosis.66 Therefore, better mapping of stenoses in 3D may provide a better assessment of its likely impact. Performing this type of research in the post-mortem setting will improve our ability to assess the significance of lesions but may also provide a useful model to inform clinical practice.

Figure 1. An image from a fluoroscopic series showing a catheter inserted into the orifice of the right coronary artery (RCA) of a cadaver (white arrow) and a pressure wire inserted into the RCA (black arrows). Pressure changes in the RCA secondary to pump injection of air/contrast in the ascending aorta can then be measured.

This raises a major question to post-mortem practice; how to interpret the significance of stenosis of the coronary arteries at post-mortem examination. The narrowing of a vessel appears to be a simple straightforward issue, but the full implications of stenosis are not yet fully understood. Even in clinical cardiac angiography, qualitative assessment of stenosis does not necessarily correlate with clinical significance,58,59 although there is no doubt that severe coronary artery disease does predict for coronary occlusion.60 It has been acknowledged that the functional significance of a vessel narrowing is more important than the actual narrowing; but as symptoms and clinical consequences vary between patients, gaining a full understanding of this is difficult. This is a key clinical question when assessing patients for suitability for a coronary artery stent. Current clinical investigations are now focused on the physiological impact of

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Post-mortem imaging does not lend itself to the type of functional imaging used in clinical cardiac stress studies, but, if tissue perfusion can accurately be shown, then its deficit may indicate significant coronary artery stenosis67 (Figure 2). However, this has yet to be shown in an autopsy controlled study and may provide too many false-positives to be a useful sign as, although perfusion loss in myocardial tissue may imply a significant stenosis, there is no way of knowing whether this is old or new, or caused by technical reasons such as air bubble or post-mortem clot (as opposed to pathological thrombus). Dynamic imaging methods, including contrast studies, are becoming possible in the post-mortem setting using pressure injectors and contrast agents of differing molecular weights with different carrier molecules. However, it is rapidly becoming clear that the information obtained is not directly related to that from standard clinical studies and that the significance of tissue perfusion has to be assessed in the post-mortem setting and for all types of contrast agent. There is more flexibility in the use of contrast agents in PMCT as toxicity is not a concern, although some consideration has to be taken of the effect of any contrast medium on subsequent toxicology or DNA examination.68–70 Generally, these can be lipophilic agents (dissolved in oil), barium particles in suspension or water-soluble iodinated chelates.6 Agents, such as air or fat, that lower X-ray attenuation and appear black on traditional CT images may also be used as negative contrast agents (Figure 3). All of these agents have their advantages and disadvantages. The key issues are related to their molecular size, viscosity, density and osmolality, which all dictate how they disperse in the body (pharmacokinetics). Currently, two broad approaches are used: the first is based on standard water-soluble agents in aqueous medium and the second uses water-soluble agents in a larger carrier solution, such polyethyleneglycol or lipophilic agents in oil. In clinical practice, water-soluble agents disperse rapidly from the intravascular space into the extravascular extracellular

Figure 2. Cardiac images, in two different cases, of autopsy proven myocardial infarction, using (a) water-soluble contrast agent and (b) lipophilic contrast agent in paraffin oil. The water-soluble agent “enhanced” the normal myocardium showing perfusion deficits (*) relating to ischaemia, whereas the normal myocardium is not enhanced by the lipophilic agent, and at autopsy no oil was identifiable in the capillaries.

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Figure 3. Whole-body angiography using (a) lipophilic contrast in paraffin oil (case of ruptured aortic aneurism) and (b) air (no vascular abnormality).

space (or interstitial space). This provides good tissue contrast, particularly where this vascular leak is rapid in one area compared with the adjacent tissues. This, however, requires rapid (dynamic) imaging after contrast agent delivery or there will be general dispersal in the tissues reducing this early “contrast”. This is particularly important if purely vascular information is required. Contrast agents have been developed for clinical MRI scanning that leak more slowly into the extravascular extracellular space. Similar leakage into the interstitial space is noted in post-mortem contrast-enhanced imaging, although the pharmacokinetics are unlikely to be identical. Although this potentially allows imaging of tissue perfusion (Figure 2), it also presents two problems, particularly for whole body imaging: ﬁrstly, considerable dispersal will occur during the time required to pump the tracer around the body thereby reducing contrast in the image; and secondly, this leakage may cause alterations in osmolality in the interstitial space thereby causing oedema and histological changes that would affect subsequent autopsy results. This has been observed in whole-body studies but not localized targeted studies, presumably because of the lower amount of agent used.48,49,71 To overcome this extravasation into the surrounding tissues, in whole-body studies polyethylene glycol has been added as a solvent72,73 or, alternatively, a lipophilic iodinated contrast agent dissolved in parafﬁn oil. Using different solvents, the viscosity can be changed allowing the agent to enter capillaries and changing the information gained.74 However, to enable post-mortem contrast-enhanced imaging to follow clinical practice, it is important that more is understood about the dispersal patterns of these contrast agents and what this means in a pathophysiological sense. For example, contrast enhancement in normal tissues is common using water-soluble media but is exceptional using contrast in oily carriers where the contrast agent does not access the capillary bed as a result of the increase of viscosity (Figure 2b). However, exceptional soft tissue enhancement does occur in the brain, the renal cortex and the left ventricular myocardium, and may indicate dilatation of precapillary arterioles at the time of death.72,73 It is possible that these contrast enhancement patterns will reveal information regarding physiology such as left ventricular hypertrophy, but

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Figure 4. Images of the heart before (a) and after (b) lipophilic contrast in paraffin oil showing atypical myocardial enhancement in a case of death owing to hypertensive heart disease and obesity.

Although these articles demonstrated the diagnostic advantages of applying such a technique, particularly in clearing background lung changes, they reported a number of potential problems ranging from the method of ventilation to movement artifact and gastric dilatation. We now routinely use this technique but have developed a technique for using supraglottic airways in all cases and use a ventilator set at 40 mBar constant pressure to avoid motion artefact.92 The images are appealing as they clear background pulmonary changes without affecting signiﬁcant pathology (Figure 5). We anticipate that this approach may not only be useful in the diagnosis of traumatic and “natural” respiratory disease but also as a useful “dynamic” model to study diseased lung to aid clinical practice.

this will require confirmation specific to the type of contrast agent and carrier it is injected with (Figure 4). Another avenue that may indicate the significance of cardiac ischaemia is the use of MRI. Early work was not autopsy controlled,75 while later articles were less optimistic,4 but, more recently, changes on T2 weighted images have been shown in animal models and clinical studies.76–78 Clinical MRI scanning tells us that there may be more complex contrast enhancement changes that may be seen, such as the delayed myocardial enhancement occurring in regions of myocardial infarction.79 Whole body contrast angiography is possible,80 and there is no reason that targeted techniques cannot be translated to MRI, except for cost and time. Interestingly, information on coronary arteries has also been obtained without angiography, by using the absence of “chemical shift” artefact as a sign of a stenosed vessel.81 Whether this turns out to be a helpful post-mortem or clinical sign82 remains to be seen, but a clear message arising from this section is that post-mortem imaging has a lot to learn from advanced clinical imaging techniques. Furthermore, clinical imaging potentially has a lot to learn from post-mortem imaging, which may provide a good research model of human disease with which to test clinical paradigms.

OTHER APPROACHES There are many developments occurring in clinical imaging. Clearly, those related to targeted injectable tracers, such as nuclear medicine studies cannot be translated to the post-mortem setting. We have already discussed that, where translation is possible in the case of injected contrast agents, circulation pharmacokinetics may be different and require systematic re-evaluation for every new agent and setting. New cardiac imaging techniques such as OCT and intravascular ultrasound can be exploited. Two further new imaging modalities currently being tested in the post-mortem setting are dual source CT and developments in MRI scanning.

Figure 5. Post-mortem CT studies in two cases: normal (a, b) and with pneumonia (c, d) documented during autopsy. The second image of each case (b, d) is after lung ventilation using a supralaryngeal airway and continuous ventilation pressure of 40 mBar and shows clearing of normal background lung changes (b) but not pneumonia changes (d).

RESPIRATORY IMAGING AND VENTILATION Clinically, most chest CT scanning is performed during breathhold after inspiration to clear atelectasis and “dependent” changes. This makes interstitial or nodular changes more apparent. Occasionally, both inspiration and expiration scans are performed to obtain functional information, such as for emphysema and air trapping.83,84 Post-mortem scans may have obscuration of lung pathology owing to increase in pulmonary opaciﬁcation (livor mortis), which can be mistaken for aspiration, pulmonary oedema or pneumonia.85 These changes build up with greater delay from death to scan,86 and the best interpretation of lung pathology has been shown within 2 h of death.87,88 Pulmonary diagnosis is therefore perceived to be difﬁcult in most cases.38 Being able to mimic ventilation in PMCT is therefore appealing to improve both the visibility of pathology and to provide functional information. Germerott et al89–91 published a novel method called ventilation-PMCT using a portable homecare ventilator delivering intermittent pressures up to 40 mBar.

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Dual source CT Dual source CT was developed mainly to increase scan speed, but it does have the advantage of easily allowing “dual energy” CT. However, as the major obstacle to dual energy CT for single scanners is movement, dual energy PMCT can be performed on most “single source” modern scanners. The advantage of using dual energy is that if X-ray attenuation is known for two X-ray energies, the information gained is much more speciﬁc to the type of material. Dual energy CT can therefore separate materials of similar appearance, such as calcium and contrast agents, and identify foreign bodies. This makes contrast perfusion patterns more reliable and is being used clinically for both cardiac and lung perfusion studies. However, a key advantage for general indications is the better discrimination of soft tissues, a weakness of CT compared with MRI.93–95 Whether dual source imaging becomes an essential component of postmortem investigation is unclear, but it is likely to become an option on all clinical scanners and therefore for PMCT. MR spectroscopy and diffusion weighted MRI MRI allows morphological information to be obtained, in a similar fashion to CT. The great advantage of MRI, and possibly its curse in terms of cost and complexity, is the ability to image using multiple tissue contrast mechanisms. These contract mechanisms in the post-mortem setting are well reviewed elsewhere in this issue.96 Two speciﬁc methods of MRI, MR spectroscopy (MRS) and “diffusion-weighted imaging” (DWI), provide potential information related to physiology and function in clinical practice. Although developed some time ago, their clinical utility is still increasing owing to advancing technology, and both techniques are now becoming available in all parts of the body and are simpler to use. MRS can give information related to molecular concentrations in a selected region, and this information can be registered with the anatomical images. Common metabolites that can be measured are lactate and choline, which link to ischaemia and cancer proliferation. More complex clinical MRI systems can test concentrations of metabolites related to other nuclei such as phosphorous. Considering these tools have been available to clinicians for many years, they are not widely used outside very

narrow indications. However, MRS is becoming easier to perform and will become available to forensic investigators using clinical MR scanners. It remains to be seen whether these techniques will be useful and justify their cost and complexity. Diffusion-weighted MRI is sensitive to microscopic water diffusion and therefore to tissue structure and cellularity. The technique can also use the asymmetry of diffusion caused by nerve sheaths (diffusion tensor imaging) to create maps of these nerve tracts (diffusion-weighted tractography). Clinically, DWI has multiple applications relating to ischaemia, cancer and discrimination of other pathologies, and its use is increasing because it is becoming easier to use in all parts of the body, not just the brain. There is evidence that these techniques can be used in the post-mortem setting, although the normal post-mortem appearance is radically different to the clinical normal, but may help with both time from death and cause, particularly in relation to the brain.29,97–99 CONCLUSIONS What is clear from the multitude of research avenues is that the scientific community is still a long way from understanding the detailed post-mortem physiological changes that dictate tissue changes, contrast dispersal patterns and complex imaging findings. However, much has been learnt, and there is no doubt that imaging should be used in many different indications in the investigation of death. There is also no doubt that post-mortem imaging can be used to inform clinical practice, not just in the traditional manner of reviewing the medical care of an individual death, but as a model to investigate epidemiology, human disease processes and their treatment. Research will undoubtedly continue in testing the diagnostic ability of new techniques, and hopefully use these strategies to impact on clinical care. However, probably the most difficult type of research is to show that new techniques have an impact on public health.100 This needs to be done by specifically validating techniques for all the indications they are required for.

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stenosis: a randomized trial. Circulation 2001; 103: 2928–34. Pijls NH. Fractional flow reserve after previous myocardial infarction. Eur Heart J 2007; 28: 2301–02. doi: 10.1093/eurheartj/ehm333 Tonino PA, Fearon WF, De BB, Oldroyd KG, Leesar MA, Ver Lee PN, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010; 55: 2816–21. Pijls NH, van SP, Manoharan G, Boersma E, Bech JW, Van’t VM, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007; 49: 2105–11. doi: 10.1016/j.jacc.2007.01.087 Adlam D, Joseph S, Robinson C, Rousseau C, Barber J, Biggs M, et al. Coronary optical coherence tomography: minimally invasive virtual histology as part of targeted postmortem computed tomography angiography. Int J Legal Med 2013; 127: 991–96. doi: 10.1007/s00414-013-0837-4 Morris PD, Ryan D, Morton AC, Lycett R, Lawford PV, Hose DR, et al. Virtual fractional flow reserve from coronary angiography: modeling the significance of coronary lesions: results from the VIRTU-1 (VIRTUal Fractional Flow Reserve From Coronary Angiography) study. JACC Cardiovasc Interv 2013; 6: 149–57. doi: 10.1016/j.jcin.2012.08.024 Roberts IS, Traill Z. Minimally invasive autopsy employing postmortem CT and targeted coronary angiography: evaluation of its application to a routine Coronial service. Histopathology 2014; 64: 211–17. doi: 10.1111/his.12271 Rutty GN, Smith P, Visser T, Barber J, Amorosa J, Morgan B. The effect on toxicology, biochemistry and immunology investigations by the use of targeted postmortem computed tomography angiography. Forensic Sci Int 2013; 225: 42–7. doi: 10.1016/j.forsciint.2012.05.012 Rutty GN, Barber J, Amoroso J, Morgan B, Graham EA. The effect on cadaver blood DNA identification by the use of targeted and whole body post-mortem computed tomography angiography. Forensic Sci Med Pathol 2013; 9: 489–95. doi: 10.1007/ s12024-013-9467-x Grabherr S, Widmer C, Iglesias K, Sporkert F, Augsburger M, Mangin P, et al. Postmortem biochemistry performed on vitreous humor after postmortem CTangiography. Leg Med (Tokyo) 2012; 14: 297–303. doi: 10.1016/j.legalmed.2012.04.010

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Jackowski C, Sonnenschein M, Thali MJ, Aghayev E, von AG, Yen K, et al. Virtopsy: postmortem minimally invasive angiography using cross section techniques– implementation and preliminary results. J Forensic Sci 2005; 50: 1175–86. Jackowski C, Bolliger S, Aghayev E, Christe A, Kilchoer T, Aebi B, et al. Reduction of postmortem angiography-induced tissue edema by using polyethylene glycol as a contrast agent dissolver. J Forensic Sci 2006; 51: 1134–37. doi: 10.1111/j.15564029.2006.00207.x Jackowski C, Persson A, Thali MJ. Whole body postmortem angiography with a high viscosity contrast agent solution using poly ethylene glycol as contrast agent dissolver. J Forensic Sci 2008; 53: 465–68. doi: 10.1111/ j.1556-4029.2008.00673.x Grabherr S, Hess A, Karolczak M, Thali MJ, Friess SD, Kalender WA, et al. Angioﬁlmediated visualization of the vascular system by microcomputed tomography: a feasibility study. Microsc Res Tech 2008; 71: 551–56. doi: 10.1002/jemt.20585 Bisset R. Magnetic resonance imaging may be alternative to necropsy. BMJ 1998; 317: 1450. Jackowski C, Schwendener N, Grabherr S, Persson A. Post-mortem cardiac 3-T magnetic resonance imaging: visualization of sudden cardiac death? J Am Coll Cardiol 2013; 62: 617–29. doi: 10.1016/j.jacc.2013.01.089 Ruder TD, Ebert LC, Khattab AA, Rieben R, Thali MJ, Kamat P. Edema is a sign of early acute myocardial infarction on postmortem magnetic resonance imaging. Forensic Sci Med Pathol 2013; 9: 501–05. doi: 10.1007/s12024-013-9459-x Shiotani S, Yamazaki K, Kikuchi K, Nagata C, Morimoto T, Noguchi Y, et al. Postmortem magnetic resonance imaging (PMMRI) demonstration of reversible injury phase myocardium in a case of sudden death from acute coronary plaque change. Radiat Med 2005; 23: 563–65. Vogel-Claussen J, Rochitte CE, Wu KC, Kamel IR, Foo TK, Lima JAC, et al. Delayed enhancement MR imaging: utility in myocardial assessment. Radiographics 2006; 26: 795–810. doi: 10.1148/rg.263055047 Ruder TD, Hatch GM, Ebert LC, Flach PM, Ross S, Ampanozi G, et al. Whole body postmortem magnetic resonance angiography. J Forensic Sci 2012; 57: 778–82. doi: 10.1111/j.1556-4029.2011.02037.x Ruder TD, Bauer-Kreutz R, Ampanozi G, Rosskopf AB, Pilgrim TM, Weber OM, et al. Assessment of coronary artery

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disease by post-mortem cardiac MR. Eur J Radiol 2012; 81: 2208–14. doi: 10.1016/j.ejrad.2011.06.042 Shriki JE, Surti KS, Farvid AF, Lee CC, Samadi S, Hirschbeinv J, et al. Chemical shift artifact on steady-state free precession cardiac magnetic resonance sequences as a result of lipomatous metaplasia: a novel finding in chronic myocardial infarctions. Can J Cardiol 2011; 27: 664–23. Zaporozhan J, Ley S, Eberhardt R, Weinheimer O, Iliyushenko S, Herth F, et al. Paired inspiratory/expiratory volumetric thin-slice CT scan for emphysema analysis: comparison of different quantitative evaluations and pulmonary function test. Chest 2005; 128: 3212–20. doi: 10.1378/ chest.128.5.3212 Prosch H, Schaefer-Prokop CM, Eisenhuber E, Kienzl D, Herold CJ. CT protocols in interstitial lung diseases—a survey among members of the European Society of Thoracic Imaging and a review of the literature. Eur Radiol 2013; 23: 1553–63. doi: 10.1007/s00330-012-2733-6 Christe A, Flach P, Ross S, Spendlove D, Bolliger S, Vock P, et al. Clinical radiology and postmortem imaging (virtopsy) are not the same: specific and unspecific postmortem signs. Leg Med (Tokyo) 2010; 12: 215–22. doi: 10.1016/ j.legalmed.2010.05.005 Shiotani S, Kobayashi T, Hayakawa H, Kikuchi K, Kohno M. Postmortem pulmonary edema: a comparison between immediate and delayed postmortem computed tomography. Leg Med (Tokyo) 2011; 13: 151–55. doi: 10.1016/ j.legalmed.2010.12.008 Shiotani S, Kohno M, Ohashi N, Yamazaki K, Nakayama H, Watanabe K, et al. Nontraumatic postmortem computed tomographic (PMCT) findings of the lung. Forensic Sci Int 2004; 139: 39–48. Michiue T, Sakurai T, Ishikawa T, Oritani S, Maeda H. Quantitative analysis of pulmonary pathophysiology using postmortem computed tomography with regard to the cause of death. Forensic Sci Int 2012; 220: 232–38. doi: 10.1016/j.forsciint.2012.03.007 Germerott T, Preiss US, Ebert LC, Ruder TD, Ross S, Flach PM, et al. A new approach in virtopsy: postmortem ventilation in multislice computed tomography. Leg Med (Tokyo) 2010; 12: 276–79. doi: 10.1016/j.legalmed.2010.07.001 Germerott T, Flach PM, Preiss US, Ross SG, Thali MJ. Postmortem ventilation: a new method for improved detection of pulmonary pathologies in forensic imaging. Leg

Med (Tokyo) 2012; 14: 223–28. doi: 10.1016/j.legalmed.2012.03.003 91. Germerott T, Preiss US, Ross SG, Thali MJ, Flach PM. Postmortem ventilation in cases of penetrating gunshot and stab wounds to the chest. Leg Med (Tokyo) 2013; 15: 298–302. doi: 10.1016/ j.legalmed.2013.08.002 92. Robinson C, Biggs MJ, Amoroso J, Pakkal M, Morgan B, Rutty GN. Post-mortem computed tomography ventilation; simulating breath holding. Int J Legal Med Nov 2013. Epub ahead of print. doi: 10.1007/ s00414-013-0943-3 93. Persson A, Jackowski C, Engstrom E, Zachrisson H. Advances of dual source, dual-energy imaging in postmortem CT. Eur J Radiol 2008; 68: 446–55. doi: 10.1016/ j.ejrad.2008.05.008 94. Johnson TR, Krauss B, Sedlmair M, Grasruck M, Bruder H, Morhard D, et al. Material differentiation by dual energy CT: initial experience. Eur Radiol 2007; 17: 1510–17. doi: 10.1007/s00330-0060517-6 95. Ruder TD, Thali Y, Bolliger SA, SomainiMathier S, Thali MJ, Hatch GM, et al. Material differentiation in forensic radiology with single-source dual-energy computed tomography. Forensic Sci Med Pathol 2013; 9: 163–69. doi: 10.1007/s12024-0129398-y 96. Ruder TD, Thali MJ, Hatch GM. Essentials of forensic post-mortem MR imaging in adults. Br J Radiol Nov 2013. Epub ahead of print. 97. Schmidt TM, Fischer R, Acar S, Lorenzen M, Heinemann A, Wedegartner U, et al. DWI of the brain: postmortal DWI of the brain in comparison with in vivo data. Forensic Sci Int 2012; 220: 180–83. doi: 10.1016/j. forsciint.2012.02.022 98. Scheurer E, Lovblad KO, Kreis R, Maier SE, Boesch C, Dirnhofer R, et al. Forensic application of postmortem diffusionweighted and diffusion tensor MR imaging of the human brain in situ. AJNR Am J Neuroradiol 2011; 32: 1518–24. doi: 10.3174/ajnr.A2508 99. Kobayashi T, Shiotani S, Kaga K, Saito H, Saotome K, Miyamoto K, et al. Characteristic signal intensity changes on postmortem magnetic resonance imaging of the brain. Jpn J Radiol 2010; 28: 8–14. doi: 10.1007/s11604-0090373-9 100. Mackenzie R, Dixon AK. Measuring the effects of imaging: an evaluative framework. Clin Radiol 1995; 50: 513–18.

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BJR Received: 7 July 2014

Accepted: 5 January 2015

doi: 10.1259/bjr.20140477

Cite this article as: Faggioni L, Neri E, Bargellini I, Scalise P, Calcagni F, Mantarro A, et al. iPad-based primary 2D reading of CT angiography examinations of patients with suspected acute gastrointestinal bleeding: preliminary experience. Br J Radiol 2015;88:20140477.

FULL PAPER

iPad-based primary 2D reading of CT angiography examinations of patients with suspected acute gastrointestinal bleeding: preliminary experience 1

L FAGGIONI, MD, PhD, 1E NERI, MD, 1I BARGELLINI, MD, 1P SCALISE, MD, 1F CALCAGNI, MD, 1A MANTARRO, MD, G D’IPPOLITO, MD and 1C BARTOLOZZI, MD

2 1

Department of Diagnostic and Interventional Radiology, University of Pisa, Pisa, Italy Department of Imaging Diagnosis, Federal University of São Paulo, São Paulo, Brazil

Address correspondence to: Dr Lorenzo Faggioni E-mail: lfaggioni@sirm.org

Objective: To evaluate the effectiveness of the iPad (Apple Inc., Cupertino, CA) for two-dimensional (2D) reading of CT angiography (CTA) studies performed for suspected acute non-variceal gastrointestinal bleeding. Methods: 24 CTA examinations of patients with suspected acute gastrointestinal bleeding confirmed (19/24, 79.2%) or ruled out (5/24, 20.8%) by digital subtraction angiography (DSA) were retrospectively reviewed by three independent readers on a commercial picture archiving communication system (PACS) workstation and on an iPad with Retina Display® 64 GB (Apple Inc.). The time needed to complete reading of every CTA examination was recorded, as well as the rate of detection of arterial bleeding and identification of suspected bleeding arteries on both devices. Results: Overall, the area under the receiver operating characteristic curve, sensitivity, specificity, positive- and negative-predictive values for bleeding detection were

not significantly different while using the iPad and workstation (0.774 vs 0.847, 0.947 vs 0.895, 0.6 vs 0.8, 0.9 vs 0.944 and 0.750 vs 0.667, respectively; p . 0.05). In DSA-positive cases, the iPad and workstation allowed correct identification of the bleeding source in 17/19 cases (89.5%) and 15/19 cases (78.9%), respectively (p . 0.05). Finally, the time needed to complete reading of every CTA study was significantly shorter using the iPad (169 6 74 vs 222 6 70 s, respectively; p , 0.01). Conclusion: Compared with a conventional PACS workstation, iPad-based preliminary 2D reading of CTA studies has comparable diagnostic accuracy for detection of acute gastrointestinal bleeding and can be significantly faster. Advances in knowledge: The iPad could be used by oncall interventional radiologists for immediate decision on percutaneous embolization in patients with suspected acute gastrointestinal bleeding.

Tablet computers are emerging as promising devices for mobile visualization of medical images from crosssectional modalities (such as CT and MRI), owing to their good screen resolution, larger display size than that of conventional smartphones and excellent power-to-weight ratio.1 Among them, the iPad (Apple Inc., Cupertino, CA) has gained wide popularity in the medical community owing to its high screen resolution (.3 MP, i.e. comparable to regular radiological workstations), its reasonably fast processor and large storage capacity (allowing browsing smoothly through large image data sets) and the availability of digital imaging and communications in medicine (DICOM)-compliant apps for image viewing and sharing that can retrieve DICOM images via wireless networks or cloud services connected to a picture archiving communication system (PACS) infrastructure. A potential perspective of this technological evolution is the usage of

tablets in a teleconsultation setting for remote twodimensional (2D) reading of emergency CT examinations, requiring fast, on-the-ﬂy reviewing of images in the absence of a dedicated workstation.2,3 In this respect, evidence exists in the literature that the iPad can successfully be used for 2D reading of emergency pulmonary CT angiography (CTA), head CT and spinal MRI studies, with a diagnostic accuracy comparable to regular PACS workstations.4–7 Acute non-variceal gastrointestinal bleeding (ANVGIB) is a life-threatening condition associated with elevated morbidity and mortality rates, requiring immediate diagnosis and treatment. CTA is now considered the mainstay for ANVGIB diagnosis owing to its high diagnostic accuracy in detection of acute arterial bleeding, thus helping to optimize treatment planning.8–10 Digital subtraction angiography (DSA) followed by transcatheter embolization of the bleeding source is

Full paper: iPad-based primary 2D reading of CT angiography examinations

increasingly recommended as the most appropriate treatment of ANVGIB and should be carried out as soon as possible to stop the bleeding, minimize the chance of bleeding recurrence and possibly improve the patient’s outcome. The feasibility of the endovascular treatment is established based on the patient’s clinical parameters and vascular anatomy and should be assessed by dedicated vascular interventional radiologists owing to its invasiveness and its potential complications.8–14 However, such specialists are not always physically available in every hospital unit on a 24/7 basis, making prompt remote consultation of CTA examinations by a vascular interventional radiologist a vital issue. In this scenario, remote tablet-based preliminary 2D reading of CTA studies of patients with suspected ANVGIB by on-call interventional radiologists could be a time-saving and costeffective solution for the management of such patients. Our aim was to assess the performance of the iPad for preliminary 2D reading of emergency CTA studies of patients with suspected ANVGIB in terms of diagnostic accuracy and image reading time compared with a conventional PACS workstation. METHODS AND MATERIALS Patient selection and CT angiography protocol 24 CTA examinations of patients (17 males and 7 females aged between 50 and 84 years; mean age, 64 years) with suspected ANVGIB performed at the Department of Diagnostic and Interventional Radiology of the University of Pisa, Pisa, Italy, were retrospectively retrieved from the PACS (Synapse; Fujifilm, MI, Italy). All CTA studies had been carried out in an emergency setting on a 64-row CT scanner (LightSpeed VCT®; GE Healthcare, Milwaukee, WI) consecutively from March 2009 to February 2013 and had been followed in all cases by DSA to confirm diagnosis and perform transcatheter embolization of the bleeding site, where present. Out of them, active arterial bleeding was confirmed by DSA in 19/24 cases (79.2%) and ruled out in the remaining 5/24 cases (20.8%). Every CTA examination consisted of a pre-contrast scan of the entire abdomen followed by a triple-phase post-contrast acquisition (consisting of an arterial, a venous and a late phase) over the same imaging volume for bleeding detection and characterization. The same scanning parameters (tube voltage, 100–120 kV depending on the patient’s weight; tube current, 100–600 mA with angular and z-axis modulation; detector configuration, 64 3 0.625 mm; detector collimation, 1.25 mm; reconstruction interval, 0.625 mm; beam pitch, 0.984:1) and contrast medium injection protocol {100–120 ml of iodixanol 320 mg of iodine per millilitre [VISIPAQUE™ (iodixanol) injection 320; GE Healthcare, Oslo, Norway] administered at 4–5 ml s21 flow rate via an 18-gauge needle in the antecubital vein, followed by 40 ml of saline flush injected at the same flow rate using a power injector} were used in all cases. Accurate timing of contrast medium injection with the beginning of every CTA scan was ensured by bolus tracking in the upper abdominal aorta with a density threshold of 150 HU and a scan delay of 10 s. Digital subtraction angiography DSA was performed in all patients within 1 h after CTA using a 5-French femoral approach on Advantx LC Vascular (GE

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Healthcare) and Innova (GE Healthcare) units. Diagnostic angiograms of the coeliac trunk and the superior and inferior mesenteric arteries were obtained using a 5-French catheter in order to locate the bleeding source as detected at CTA, followed by superselective catheterization of the culprit vessel(s) with a 3-French microcatheter in all cases. Image reading All CTA data sets (including source axial images and multiplanar reformatted series where available, but maximum intensity projection and volume rendering reconstructions were excluded to avoid any potential facilitation in diagnosis) were anonymized and exported in DICOM format on a dedicated commercial workstation (Advantage Windows® 4.6; GE Healthcare, Fairfield, CT) for retrospective image analysis. The same anonymized data sets were also transferred to a PACS server (iMac® 27-inch; Apple Inc.) connected to our hospital PACS running OsiriX 64-bit v. 5.8 (www.osirix-viewer.com) and then exported wirelessly in DICOM format with JPEG 2000 lossless compression to an iPad with Retina Display® 64 GB (Apple Inc.) running OsiriX HD® v. 4.0.2 (www.osirix-viewer.com) using the Bonjour® protocol (Apple Inc.). Three radiologists with experience of more than 5 years in vascular and gastrointestinal radiology independently reviewed all CTA data sets on the workstation. None of the readers had previously read any of the CTA examinations or performed DSA on any of the patients involved in the study, and all of them were blinded to DSA findings or any other information related to the patients’ clinical condition (including parameters such as haemoglobin levels and blood pressure) or previous imaging findings. In order to reasonably prevent any memory effect by the readers, each of them reviewed the same data sets independently in a random order on the iPad under the same lighting conditions 4 weeks after the end of the first round of CTA image readings. Prior to the beginning of the image reading session on the iPad, the iPad screen had been calibrated using a dedicated application (MediCal QAWeb Mobile®; Barco Srl, Milan, Italy). Moreover, all readers had previously undergone a 1-month period of training on CT image reading on the iPad, as empirically deemed sufficient so as to gain adequate self-confidence and speed in CT image reading on the iPad. In both image reading sessions, all readers had been instructed to mark all cases as positive or negative related to the CTA finding of active arterial bleeding (defined as contrast medium blush in the arterial phase growing in the subsequent postcontrast acquisitions), as well as to indicate the most likely source of bleeding in terms of the major artery likely feeding the suspected “culprit” vessel (classified as coeliac trunk, left/right gastric artery, gastroduodenal artery, pancreatoduodenal arteries, superior mesenteric artery and inferior mesenteric artery) (Figures 1–3). Any additional finding other than the suspected active arterial bleeding was ignored. In case of disagreement among readers with either device, agreement was reached through consensus reading.

Br J Radiol;88:20140477

BJR Received: 17 February 2014

Accepted: 23 July 2014

doi: 10.1259/bjr.20140150

Cite this article as: Dhikav V, Sethi M, Anand KS. Medial temporal lobe atrophy in Alzheimer’s disease/mild cognitive impairment with depression. Br J Radiol 2014;87:20140150.

SHORT COMMUNICATION

Medial temporal lobe atrophy in Alzheimer’s disease/mild cognitive impairment with depression V DHIKAV, PhD, M SETHI, MBBS and K S ANAND, DM Memory Clinic, Department of Neurology, Dr Ram Manohar Lohia Hospital, Postgraduate Institute of Medical Education and Research, University School of Medicine & Paramedical Health Sciences, Guru Gobind Singh Indraprastha University, New Delhi, India Address correspondence to: Dr Vikas Dhikav E-mail: vikasdhikav@hotmail.com

Objective: Depression is common in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Patients with depression have an earlier onset and rapid progression of cognitive decline. Medial temporal lobe atrophy (MTA) is common in AD and MCI, and some degree of atrophy is found in almost all patients. In the present study, an attempt was made to know if MTA is more common in patients with AD/MCI with depression than those without it. Methods: Patients reporting to the outpatient department of a neurology centre of a tertiary care hospital were recruited for the present study. After initial general physical and neurological examination, they were evaluated using National Institute of Neurological and Communicative Disorders and Stroke and Related Disorders Association criteria for diagnosis of AD. Clinical Dementia

rating scale was used for the diagnosis of MCI. Cornell scale for depression in dementia (CSDD) was used. Results: We found 20 cases with depression as per CSDD out of a sample of 37 patients (male:female 5 30:7). There were 26 patients with AD and 11 with MCI. The mean age of all patients was 72.33 6 6.45 years. The mean mini mental status examination score was 19.00 6 6.73. The mean time since diagnosis was 4.19 6 3.26 years. The mean Scheltens visual rating scale score for right MTA was 2.08 6 0.95 and was 2.05 6 0.94 for the left. Both scores did not differ statistically when analyzed using paired t-test (p . 0.05). However, difference in those with depression (2.36 6 0.95) from those without depression (1.60 6 0.74) was significant (p , 0.05). Conclusion: MTA scores were higher in those with AD/MCI with depression than those without it.

Depression1 is common in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Relationship between depression and cognitive decline is a complex one, and depression is both an aetiological risk factor2 and comorbidity for dementia.3 Incidence and prevalence of depressive symptoms in MCI range from 15% in population-based studies to 44% in hospital-based studies.4 Likewise, up to two-thirds of patients with AD have been reported to have depression.5 Because in many studies, depression has been seen to be an early manifestation of AD, it has been suggested that it may represent a continuum4 from depression to MCI to AD (late-life depression → MCI → AD). Two recent meta-analyses have found that a history of depression approximately doubles an individual’s risk for subsequent dementia in general and AD in particular.6 Depression is known to be neurotoxic to medial temporal lobe structures and can contribute to their atrophy.7–9 Atrophy is more so, when depression is severe or recurrent7 and medial temporal lobe atrophy (MTA) has a temporal association with depression.9 Continued treatment of depression has been shown to protect the

hippocampus from the ill effects of depression.10 Although volumetric method could be a preferred mode of measuring the hippocampal volume in AD, qualitative rating of MTA is a good alternative.11 Visual rating of the hippocampal volume12–14 can be carried out using Scheltens et al15 rating scale that is based on the width of the choroid ﬁssure, the width of the temporal horn and the height of hippocampal formation and is a quantitative scale. METHODS AND MATERIALS Patients reporting to the outpatient department of a neurology centre of a tertiary care hospital were recruited for the present study. Subjects were selected randomly and from the general outpatient department, and they were asked to attend a specialized memory clinic. After initial general physical and neurological examination, they were evaluated using the National Institute of Neurological and Communicative Disorders and Stroke and the Related Disorders Association (NINCDS-ARDA) criteria for the diagnosis of AD.2 Clinical Dementia Rating scale5 was used for the diagnosis of MCI (0.5 score on Clinical Dementia

Short communication: Medial temporal lobe atrophy in AD/MCI

Rating scale). Cornell Scale for Depression in Dementia (CSDD) was used for assessing depression in dementia (internal consistency, 0.84; predictive validity—sensitivity, 0.90; specificity, 0.75). CSDD contains 19 items with a maximum score of 2 each, therefore, the maximum possible score is 38. The scale has high inter-rater reliability (0.67). Depression was evaluated using CSDD, which is considered the gold standard in assessing depression in dementia. CSDD is the best-validated instrument for measuring depression in dementia7 and takes into account the fact that some symptoms of dementia can mimic those of depression. It involves comprehensive semi-structured interviewing approach and integrates the patient and caregiver interviews to reach a composite clinician rating. Probable depression in the present study was defined as a score of CSDD .10. MTA described by Scheltens et al15 (Table 1) uses hard copies of MRI coronal sections. The scale has high inter-rater and intrarater reliability.15 It has been validated both in linear and volumetric measures of the medial temporal lobe. Some studies indicate that the visual method of medial temporal lobe estimation is as good as detailed volumetric measurements.15 Comparisons of clinical diagnosis made by NINCDS-ARDA criteria and MTA scores were performed to know the diagnostic accuracy of the MTA scores. MTA (right and left) Scheltens visual rating using MRI brain coronal sections was carried out by an experienced neurologist with 30 years’ experience. It was found that MTA scoring had high sensitivity [88–95% confidence interval (CI) 5 68–94%] and specificity (86% CI 5 68–94%) in diagnosing dementia of probable Alzheimer’s type using NINCDS-ARDA criteria. It is well known that definite diagnosis of AD can only be made by histopathology. However, clinical diagnosis of probable, possible and unlikely Alzheimer’s can be diagnosed using NINCDS-ARDA criteria. Sensitivity and specificity calculated in this study is in agreement with data reported earlier.7 RESULTS There were 26 patients with AD and 11 with MCI. The mean age of all patients was 72.33 6 6.45 years. 20 cases with depression as per CSDD out of a sample of 37 patients (male:female 5 30:7) were found (54%). The mean mini mental status examination

BJR

(MMSE) score was 19.00 6 6.73. Mean time since diagnosis was 4.19 6 3.26 years. Data were checked for normalcy using interquartile range (IQR) for both sets (non-depressed and depressed). The IQR for the non-depressed set was 1.5 and the median was also 1.5, whereas the IQR for the depressed set was 1 and the median was 2.5. These values represent a normal distribution as there were no outliers. The latest version of SPSS® (SPSS Inc., Chicago, IL) was used for data analysis. The mean Scheltens visual rating scale score for the right MTA was 2.08 6 0.95 and 2.05 6 0.94 for the left. Both of them did not differ statistically when using paired t-test (p . 0.05). However, the difference in those with depression (2.36 6 0.95) from those without depression (1.60 6 0.74) was significant (p , 0.05). Pearson’s correlation coefficient between the left and right MTA was calculated to be 0.45, and the coefficient of determination (r2) was 0.2. This suggests a weak relationship between the left and right MTA scores (Figure 1). This was consistent with the insignificant difference between the left and right MTA scores. DISCUSSION Depression is a common comorbidity seen in AD/MCI.11 It can precede the development of dementia or can present along with it. The loss of hippocampal volume and memory functions observed in some elders in late-life depression suggests the possibility that depression may be a predisposing risk factor for AD in particular. Lower hippocampal volumes independently predict subsequent AD in groups of MCI and cognitively normal elderly subjects.7 The present study reports MTA using Scheltens visual rating scale for MTA. Smaller volume in the present study could perhaps be owing to hypercortisolemia,12–14 as reduced hippocampal volume may no longer be able to inhibit hypothalamic pituitary adrenal axis. An increase in cortisol notably promotes apoptosis and neurodegeneration and encourages deposition of

Figure 1. Scatter plot for correlation between the left and right medial temporal lobe atrophy scores as per Scheltens visual rating scale.

Table 1. Scheltens visual rating scale for medial temporal lobe atrophy15 Score 0: no atrophy (no atrophy) Score 1: only widening of choroid ﬁssure (minimal atrophy) Score 2: also widening of temporal horn of lateral ventricle (moderate atrophy) Score 3: moderate loss of hippocampal volume (decrease in height—severe atrophy) Score 4: severe volume loss of hippocampus (marked atrophy)

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Br J Radiol;87:20140150

BJR Received: 19 March 2013

Accepted: 27 June 2013

doi: 10.1259/bjr.20130163

Cite this article as: Mori S, Inaniwa T, Furukawa T, Zenklusen S, Shirai T, Noda K. Effects of a difference in respiratory cycle between treatment planning and irradiation for phase-controlled rescanning and carbon pencil beam scanning. Br J Radiol 2013;86:20130163.

FULL PAPER

Effects of a difference in respiratory cycle between treatment planning and irradiation for phase-controlled rescanning and carbon pencil beam scanning S MORI, PhD, T INANIWA, PhD, T FURUKAWA, PhD, S ZENKLUSEN, PhD, T SHIRAI, PhD and K NODA, PhD Medical Physics Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan Address correspondence to: Dr Shinichiro Mori E-mail: shinshin@nirs.go.jp

Objective: To evaluate the impact of variation in respiratory cycle between treatment planning and irradiation for pencil beam scanning and phase-controlled rescanning (PCR) on the resulting dose distribution, we conducted a simulation study based on four-dimensional CT (4DCT) data for lung cancer patients. Methods: 4DCT data were acquired for seven patients with lung tumours. Treatment planning was designed to ensure the delivery of 95% of the prescribed dose to the clinical target volume in respective phases of the 4DCT by taking account of intrafractional beam range variations. Carbon ion pencil beam scanning dose distributions were calculated for various respiratory cycles that differed from the reference respiration (54.4 s) but which stayed regular during irradiation. The number of rescannings was changed to 1, 4 or 8 times. PCR was correlated with the gating window in treatment planning to calculate the beam weighting map.

Results: 83PCR improved dose conformation to the target for all irradiation respiratory cycles. Minimum dose (Dmin) and lowest dose encompassing 95% of the target (D95) values with 43PCR were decreased from 94.1% and 98.1% to 88.4% and 93.5% with an altered irradiation respiratory cycle of 2.4 s. However, these values were improved with 83PCR to over 94.9% for Dmin and 98.6% for D95 for respective irradiation respiratory cycles. Conclusion: Pencil beam scanning treatment with eight or more PCRs consistently improved dose conformation for moving lung targets even when different respiratory cycles were used for treatment planning and irradiation. Advances in knowledge: Scanning treatment with eight or more rescannings consistently improved dose homogeneity to a moving target even though respiratory cycles varied during treatment.

Charged particle beams provide superior dose conformation to photon beams, and more than 28 particle treatment centres have now been established worldwide. Since 1994, our centre at Heavy Ion Medical Accelerator in Chiba, Japan, has treated over 7000 cancer patients using carbon ion passive beams [1–3]. In 2011, we constructed a new treatment facility for carbon ion pencil beam scanning (C-PBS) as an extension of the existing treatment facility and successfully completed the ﬁrst clinical trials for the head and pelvic regions with non-respiratory-gated irradiation at the end of 2011 [4,5]. We are now preparing to start the next series of clinical trials for the thoracic and abdominal regions.

owing to its movement in and out of the beam ﬁeld with respiration. Second, because the stopping position of a charged particle beam is strongly dependent on the radiological pathlength from the patient surface, replacing dense tissue with a low-density material such as lung causes a signiﬁcant change in radiological pathlength, resulting in the perturbation of beam stopping position from that originally planned. Although passive scattering beam irradiation delivers homogeneous three-dimensional (3D) dose distributions that cover the whole tumour region at any time, C-PBS delivers respective beam spots as a function of time. Scanning irradiation is accordingly less robust against organ motion than passive beam delivery owing to interplay effects that cause hot and/or cold spots within the target owing to the inconsistency between beam motion and target motion [6]. Proposed remedies for this problem include respiratory gating, tracking [7] and rescanning [8] strategies, of which gating and rescanning are preferable from a practical point of view. For C-PBS at our institute, the beam spots are sorted and delivered in layers of spots of the same range/energy,

Organ motion is a major challenge in radiotherapy and can both degrade dose conformation within a tumour and cause excessive dosages to normal tissues. Organ motion as a result of respiratory motion is now well understood, and several problems have been recognised. First, if respiratoryinduced tumour motion is not considered in treatment planning, the treatment beam will not irradiate the tumour

Full paper: 4D scanning therapy

called isoenergy layers, on the basis that the speed of scanning in the lateral direction is much higher than the variation of range. Our approach to the moving tumour problem is a combination of layered rescanning correlated with the gating window, which we term “respiratory phase-controlled-layered rescanning (PCR)”. We measured dose distribution with PCR under a motion scenario using Gafchromic™ films (Ashland Inc., Covington, KY) in which four or more PCRs achieved dose differences of less than 2% of that with the static case [9]. Measurement showed higher target dose homogeneity for PCR than was obtained without correlated rescanning. A similar approach has been proposed for proton beam therapy [10]. However, several problems remain to be solved before clinical treatment of tumours in the thoracic and abdominal regions with C-PBS can be started. Most treatment planning processes assume that patient respiratory cycle and pattern remain reproducible throughout the course of treatment and do not address interfractional variation. The respiratory pattern is variable, however, and this may lead to rescanning of an isoenergy layer to fail to finish within a gate window, resulting in inconsistencies between treatment planning and treatment beam delivery. This remains a fundamental challenge to PCR in thoracic and abdominal treatment. Here, we evaluated the impact of respiratory cycle variation between treatment planning and treatment beam irradiation on dose distribution for four-dimensional (4D) C-PBS of a lung tumour using a 4DCT scan-based dose calculation. METHODS AND MATERIALS Rescanning methods Our centre provides integrated hybrid C-PBS [11]. This scanning method uses a mini ridge filter (to create a mini spread-out Bragg peak), a range shifter and 11 synchrotron energies. The range shifter and energy changes can be adjusted in 3- and 30mm range steps, respectively. In the present study, we set control times for the range shifter and synchrotron energy changes to 420 and 150 ms, respectively [12,13]. Hybrid scanning provides a superior lateral dose fall-off and a higher relative biological effectiveness than can be obtained with the range shifter only because less range shifter material is needed [11]. The beam characteristics are comparable with those with the sole use of the synchrotron for energy variation but require less commissioning work. PCR performs the rescanning of all spots of a layer within the gating window such that the rescanning of the layer is completed at the end of the gating window. After finishing one layer, the energy/range is changed and the next layer is irradiated. This process is repeated until all spots of the entire set of layers are delivered. To achieve this strategy, the dose rate for respective isoenergy layers is calculated from the gating window time and is set by the radiation system before the delivery of each layer. Therefore, once the treatment is started, the irradiation pattern (beam spot, dose rate, etc.) cannot be changed even though the patient respiratory pattern may have changed. Figure 1a shows the scan pattern with a perfectly regular respiratory signal for a gated PCR with two rescannings. All spots in the mth and all spots in the m11th isoenergy layers were rescanned twice within their respective gates; namely, once each in the first and

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subsequent gating window. Beam weights in the gating window within the same isoenergy layer were the same but differed from those of the respective isoenergy layers. However, if the irradiation respiratory cycle changes from that in treatment planning, not all beam spots will be completed at the end of the gating window, and PCR will not be achieved. Remaining spots will be delivered at the start of the next gate and will then be followed by energy variation during the gate window, which will further prolong treatment and desynchronize PCR, as illustrated in Figure 1b. In that case, beam spots in the mth isoenergy layer were irradiated twice, each for a shorter duration than in the ﬁrst gating window, and several spots in the m11th isoenergy layer were irradiated in the same gating window. When the irradiation respiratory cycle was shorter than the planning respiratory cycle, in contrast, beam spots in the mth isoenergy layer irradiation were completed before the end of the gating window and start of irradiation of the next isoenergy layer. PATIENTS Seven of our lung cancer patients were randomly selected (Table 1) and asked for their consent to participate in this study. The study protocol was approved by the Institutional Review Board of our institute. 4DCT was carriedout with a fast-rotating area detector CT [14] under free-breathing conditions, with patient respiration monitored using a respiratory sensing system consisting of a position-sensitive detector and an infrared-emitting light marker (PSM15010; Toyonaka Kenkyujo, Osaka, Japan). CT voxel size was 51235123128 [0.78 mm (anteroposterior) 3 0.78 mm (left–right) 3 1.0 mm (superoinferior)]. Motion parameters, including respirator cycles and Euclidian distance of the 3D centre of mass (3D-COM) of the gross tumour volume (GTV), are summarised in Table 1. Treatment planning Target definition A single respiratory cycle was subdivided into 10 equal phases (T00: peak inhalation, T50: peak exhalation). The GTV was delineated on the 4DCT data at T50. All GTV contours at other respiratory phases for the patient were then automatically calculated by B-spline-based deformable image registration (DIR) [15,16]. Clinical target volume (CTV) included the GTV plus a 10-mm margin. The beam weighting map was designed to ensure uniform dose distribution to CTVs in respective phases. The internal target volume (ITV) included the target-encompassing volume within the gating window; however, the International Commission on Radiation Units and Measurements Report 62 describes the “geometrical” rather than the “radiological pathlength” concept for ITV creation [17]. Maximum intensity volume (MIV) and average intensity projection (AIP), approaches which have been introduced in passive particle beam irradiation [18,19], were successfully used to deliver the treatment beam to a moving target using a treatment planning system that was commercially available at that time. Because these methods may result in expansion of the smeared beam ﬁeld and density regions, however, and consequently cause overdosage to the normal tissue regions, they have not been completely optimised to allow for intrafractional range variations [20]. Further, given that intrafractional dose degradation with passive beam occurs as a blurring effect, whereas scanning irradiation suffers from

Br J Radiol;86:20130163

BJR Received: 14 August 2014

Accepted: 18 November 2014

doi: 10.1259/bjr.20140547

Cite this article as: Zhu B, Sevick-Muraca EM. A review of performance of near-infrared fluorescence imaging devices used in clinical studies. Br J Radiol 2015;88: 20140547.

REVIEW ARTICLE

A review of performance of near-infrared fluorescence imaging devices used in clinical studies B ZHU, PhD and E M SEVICK-MURACA, PhD Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA Address correspondence to: Professor Eva M Sevick-Muraca E-mail: Eva.Sevick@uth.tmc.edu

ABSTRACT Near-infrared fluorescence (NIRF) molecular imaging holds great promise as a new “point-of-care” medical imaging modality that can potentially provide the sensitivity of nuclear medicine techniques, but without the radioactivity that can otherwise place limitations of usage. Recently, NIRF imaging devices of a variety of designs have emerged in the market and in investigational clinical studies using indocyanine green (ICG) as a non-targeting NIRF contrast agent to demark the blood and lymphatic vasculatures both non-invasively and intraoperatively. Approved in the USA since 1956 for intravenous administration, ICG has been more recently used off label in intradermal or subcutaneous administrations for fluorescence imaging of the lymphatic vasculature and lymph nodes. Herein, we summarize the devices of a variety of designs, summarize their performance in lymphatic imaging in a tabular format and comment on necessary efforts to develop standards for device performance to compare and use these emerging devices in future, NIRF molecular imaging studies.

Near-infrared fluorescence (NIRF) imaging is an emerging clinical technology that requires administration of a fluorescence-imaging agent that can be excited at nearinfrared (NIR) wavelengths of $760 nm. Upon illuminating tissue surfaces with penetrating NIR light to excite the imaging agent within the tissues, the generated fluorescence is collected to form a two-dimensional (2D) image demarking the tissue deposition of the NIRF imaging agent. While far-red and NIR light between the wavelength ranges of 690–900 nm penetrate deeply in tissues, endogenous chromophore fluorescence when excited by light of wavelengths ,780 nm, creates a high autofluorescence background for molecularly targeting exogenous imaging agents in tissues. The tissue depth to which the NIRF imaging can detect NIRF imaging agents is dependent upon their brightness and the sensitivity of the device, but has been estimated to be between 3 and 4 cm beneath the tissue surfaces in intensified devices1 and ,2 cm in others.2 Three-dimensional tomographic imaging using 2D projection data as well as time-dependent and independent methods has been developed for small animal imaging3,4 but, owing to these limitations in tissue penetration, has not been translated to clinical imaging.

The exciting concept of conjugating a NIR excitable fluorophore to a small molecule, protein or antibody that targets an extracellular disease marker for diagnostic, molecular imaging has been postulated for years by several investigators.5–7 The use of NIRF imaging for molecularly guided surgical resection of cancers could dramatically reduce residual tumour burden as well as surgical morbidity associated with excising sufficient tissues to avoid having positive surgical margins. However, the tissue depth, concentration and dose at which a “firstin-humans” imaging agent can be detected in tissues depends upon several factors but, most importantly, upon the sensitivity of the imaging device. Unlike positron emission tomography, scintigraphy, single-photon emission and the g probe used to detect radiolabelled molecular targeting agents for diagnostic imaging and intraoperative detection, fluorescence imaging devices do not have phantoms and standards to assess performance metrics, and there are no traceable standards to quantify or compare performance between fluorescence imaging devices. Different fluorescent imaging device designs, summarized for clinical devices in an excellent review by Alander et al,8 likely result in varying performance for detecting a NIRF imaging agent. As a result in the USA, the regulatory strategy for securing market approval of

Review article: A review of performance of near-infrared fluorescence imaging devices used in clinical studies

fluorescent imaging agents is to pair the drug approval process to a specific model of imaging device [e.g. approval of Cysview® (Photocure, Oslo, Norway) with Karl Storz blue light cystoscope (PDD system; Karl Storz GmbH and Co., Tuttlingen, Germany)]. This practice could limit the entry and adoption of molecularly targeted NIRF imaging agents into clinical practice. To date, the only NIR-excited fluorophore used clinically is indocyanine green (ICG). Since 1956, ICG has been approved by the US Food and Drug Administration for intravenous (i.v.) administration at a concentration of 2.5 mg ml21 with doses of up to 25 mg in adults, 12.5 mg in children and 6.25 mg in infants. ICG has been used in the clinic as a reagent for determining cardiac output, hepatic function and ophthalmic angiography. It has an excellent record of safety, and there is no demonstrable evidence of phototoxicity associated with its use.9 After administration, ICG binds tightly to plasma proteins and has a half-life of several minutes in blood circulation, which allows repeated intraoperative i.v. administration for fluorescence angiography. In the plasma, the absorption and emission peaks of ICG are shifted towards longer wavelengths, to around 807 and 822 nm,10 respectively, but still reside in the “optical window” of the tissues. Compared with other NIR-excited fluorophores, the quantum efficiency (QE) of ICG is low and reported to be 0.02 at 780 nm excitation and 830 nm emission;11 it is comparatively unstable once reconstituted in saline; and it has no functional group for conjugation to compound for molecular imaging. Using ICG as a non-specific blood vascular imaging agent, NIRF angiography has been used intraoperatively in coronary, neurosurgical and vascular surgeries8 as well for non-invasive assessment of superficial perfusion.12 Most recently, ICG has been used in off-label intradermal and subcutaneous administrations at varying doses for evaluating the lymphatic circulation to identify sentinel lymph nodes (SLNs) in surgical oncology,10,13,14 assess lymphovenous anastomoses (LVA) surgery15–17 and non-invasively map the lymphatic vasculature.18–20 Indeed, “ICG lymphography” has been found to be superior to lymphoscintigraphy for diagnostic imaging of early lymphoedema in upper extremities20 and enables early diagnosis of lymphoedema before the onset of symptoms.20–22 Yet, the doses of ICG and the design of devices used in these and other clinical studies vary widely, suggesting variable device performance. The available ICG fluorescence imaging devices on the market include photodynamic eye (PDE; Hamamatsu Photonics Co., Hamamatsu, Japan) and SPY (Novadaq Technologies Inc., Toronto, ON, Canada), with other investigational devices such as frequency-domain photon migration (FDPM) imager (University of Texas Health Science Center at Houston, TX) and mini-FLARE™ (Israel Beth Deaconess Medical Center, Boston, MA) also employed in clinical studies. Although the architecture can be dramatically different among these devices, the core components are (i) the light source for exciting ICG; (ii) optical filters for separating emitted fluorescent signals from strong backscattered excitation light and ambient light signals; and (iii) an area detector for sensing the emitted fluorescent signals. Undoubtedly, the performance of

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a device is ultimately determined by these core components, requiring different dosages of ICG ranging from micrograms to milligrams per injection for visualizing the lymphatics. In this review, we first compare three core components employed in various ICG fluorescence imaging systems and then review the varying ICG concentrations used in clinical imaging of the lymphatic vasculature and lymph nodes as an indicator of device performance. This review complements those of others10,13,14,23 but summarizes literature results in a tabulated and quantitative format to enable readers to compare performance. Finally, we comment on a proposal for a systematic approach to quantify and report imaging device performance using standardized measurements of certifiable phantoms that could accelerate the future translation of NIRF molecular imaging agents used with these fluorescence imaging devices. INSTRUMENTATION In order to understand differences in performance presented in the ICG imaging of lymph nodes for cancer staging and the Lymphatic imaging sections, the differences in imaging devices employed in these studies are first described. As described in past reviews,8,24 there are three core components common to the ICG fluorescence imaging systems, summarized in Table 1. These are the incident light sources used to excite ICG; the optics that allow for collection of ICG fluorescence and rejection of ambient and backscattered incident light; and the area detector used to register the collected light (Figure 1). Incident light sources for collection of indocyanine green fluorescence The commonly used excitation light sources in ICG fluorescence imaging systems in order of increasing spectral bandwidth are (i) laser diodes; (ii) light-emitting diodes (LEDs); and (iii) filtered lamp sources, which have typical spectra illustrated in Figure 1a. Because rejection of backscattered excitation light is performed spectrally through the use of interference filters, laser diodes enable the greatest sensitivity, since the “background” arising from “leakage” of backscattered excitation light is the lowest. By contrast, LEDs generate a broader band of wavelengths with relatively lower power output, requiring tens of LEDs integrated together for milliwatts per square centimetre of incident light. For the filtered lamp sources, the lamp sources are filtered to generate excitation light with a narrow band, but the generated excessive heat needs to be dissipated to extend the lifetime of the filter. In addition, the filtered lamp sources have low efficiencies, making it difficult to couple into an optical fibre. Hence, laser diodes and LEDs are widely adopted in the ICG fluorescence imaging systems used clinically. One might expect that the greater amount of incident excitation light (measured as a “fluence” in milliwatts per square centimetre) would result in more ICG fluorescence and a larger amount of collected fluorescence signal. However, there are maximum permissible exposure (MPE) limits for both eye safety as well as skin safety. The American National Standards Institute’s (#13997) MPE for eye exposure of a 700–1050 nm laser beam is 102(l20.700) 3 1023 W cm22 when the duration is between 10 and 30,000 s, and the MPE for skin exposure

Br J Radiol;88:20140547

BJR Received: 7 January 2015

Accepted: 16 March 2015

doi: 10.1259/bjr.20150025

Cite this article as: Emrich T, Emrich K, Abegunewardene N, Oberholzer K, Dueber C, Muenzel T, et al. Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries. Br J Radiol 2015;88:20150025.

FULL PAPER

Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries 1

T EMRICH, MD, 1K EMRICH, MD, 2N ABEGUNEWARDENE, MD, 1K OBERHOLZER, MD, PhD, 1C DUEBER, MD, PhD, T MUENZEL, MD, PhD and 1K-F KREITNER, MD, PhD

2 1

¨ tsmedizin, Johannes Gutenberg University of Mainz, Mainz, Germany Department of Diagnostic and Interventional Radiology, Universita ¨ tsmedizin, Johannes Gutenberg University of Mainz, Mainz, Germany Department of Cardiology, Universita

Address correspondence to: Mr Tilman Emrich E-mail: Tilman.Emrich@unimedizin-mainz.de

Objective: To assess the diagnostic value of cardiac MRI (CMR) in patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Methods: This study included a total of 125 patients treated in the chest pain unit during a 39-month period. Each included patient underwent MRI within a median of 3 days after cardiac catheterization. The MRI protocol comprised cine, oedema-sensitive and late gadolinium-enhancement imaging. The standard of reference was a consensus diagnosis based on clinical follow-up and the synopsis of all clinical, laboratory and imaging data. Results: MRI revealed a multitude of diagnoses, including ischaemic cardiomyopathy (CM), dilated CM, myocarditis, Takotsubo CM, hypertensive heart disease, hypertrophic CM, cardiac amyloidosis and non-compaction CM. MRI-

based diagnoses were the same as the final reference diagnoses in 113/125 patients (90%), with the two diagnoses differing in only 12/125 patients. In two patients, no final diagnosis could be established. Conclusion: CMR performed early after the onset of symptoms revealed a broad spectrum of diseases. CMR delivered a correct final diagnosis in 90% of patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Advances in knowledge: Diagnosing patients with acute coronary syndrome but unobstructed coronary arteries remains a challenge for cardiologists. CMR performed early after catheterization reveals a broad spectrum of diseases with only a simple and quick examination protocol, and there is a high concordance between MRIbased diagnoses and final reference diagnoses.

Acute coronary syndrome (ACS) is a common working diagnosis in emergency and chest pain units worldwide. Acute chest pain is the cardinal symptom of an ACS, but clinical ﬁndings vary among patients, ranging from mild discomfort to severe cardiac arrhythmias and sudden cardiac death. Among all patients admitted to a hospital with acute chest pain, only 30% receive a ﬁnal diagnosis of ACS.1 This is reasonable owing to the multitude of differential diagnoses for troponin-positive acute chest pain ranging from STelevation myocardial infarction to non-cardiac aetiologies, such as pulmonary embolism and sepsis.2,3

However, while ST elevations may indicate myocardial infarction, they can also be owing to other serious conditions, including pericarditis, myocarditis, cardiomyopathy (CM) and congestive heart failure. Moreover, ACS can be present even without ECG changes, for example, in cases of non-STelevation myocardial infarction (NSTEMI) or unstable angina pectoris.3–5

In addition to the examination of clinical signs and symptoms, electrocardiogram (ECG) diagnostics and troponin measurements are routinely used in ACS evaluation. Standard 12-lead ECG is a key diagnostic tool for determining which patients with suspected acute myocardial infarction should be directed to the angiography suite.4

Cardiac troponin measurement, especially with implementation of highly sensitive assays, plays a central role in establishing a diagnosis and stratifying risk in patients with ACS.6,7 However, aetiological diagnosis remains challenging in cases of troponin-positive acute chest pain with either normal coronary arteries or non-ﬂow-limiting coronary artery disease. There are many possible responsible entities, such as clot lysis and recanalization of an acute thrombotic obstruction, coronary thromboembolism, acute myocarditis, apical ballooning syndrome, coronary vasospasm, inherited

Full paper: cMRI in patients with ACS and unobstructed coronary arteries

BJR

thrombophilia, non-ischaemic cardiomyopathies and non-cardiac aetiologies.3,8

partially parallel acquisition) algorithm, with an acceleration factor of 2, and 33 reference lines.

Cardiac MRI (CMR) does not yet have a well-established role in patients with suspected ACS and is not part of the routine clinical work-up described in the current guidelines of the European Society of Cardiology.9 However, increasing evidence suggests that CMR may provide incremental diagnostic value in these patients.10–13 We have adopted CMR in the diagnostic work-up of patients with suspected ACS.

For oedema-sensitive imaging, we used a triple inversion recovery turbo spin echo sequence (TIRM) with acquisition in the same long- and short-axis planes [TE, 60 ms; TR, 2 3 RR interval; inversion time (TI), 170 ms; slice thickness, 10 mm; ﬂip angle, 180° and pixel size, 2.3 3 1.3 mm2]. The integrated body coil was used for signal detection of this sequence.

The present study aimed to investigate the diagnostic value of CMR in patients with suspected ACS. As a standard of reference, we used a consensus-based final diagnosis established using clinical follow-up of up to 3 months after admission and the synopsis of all clinical, laboratory and imaging findings. METHODS AND MATERIALS Patient recruitment We searched our data files for patients who presented with acute chest pain, elevated cardiac enzymes and non-obstructed coronary arteries at coronary angiography and who underwent CMR within a 39-month period between January 2007 and March 2010. Following current guidelines, 9 all patients underwent 12-lead ECG, determination of cardiac biomarkers and echocardiography within the first 20 min after admission to the chest pain unit. Coronary obstruction could not be ruled out in any case, even among patients without ST elevation. Therefore, all patients underwent coronary angiography within 12 h, which did not reveal relevant stenotic lesions in any case. Subsequently, CMR was performed to exclude myocardial infarction and to provide an alternative diagnosis to explain the clinical presentation without reference to the previous results. Patients with a history of myocardial infarction and chronic troponin elevation were excluded, as were any patients with standard contraindications to CMR (e.g. claustrophobia or pacemaker). All patients gave their written informed consent to undergo CMR. Owing to the retrospective study design and the fact that CMR was performed as a routine part of the diagnostic work-up in these patients, the requirement for study approval by the local ethics committee was waived. Cardiac MRI protocol CMR was performed with a 1.5-T MAGNETOM® Sonata® MRI scanner (Maestro Class; Siemens Healthcare, Erlangen, Germany) using a six-channel phased-array cardiac coil and integrated spine array coil elements for signal detection. For imaging, all patients were positioned in the supine position. Global and regional ventricular function was assessed via cine imaging using a segmented steady-state free precession pulse sequence. To cover the entire left ventricle, we acquired images in horizontal and vertical long-axis views as well as in multiple short-axis views every 10 mm. Typical inplane resolution was 2.0 3 1.5 mm2, with a section thickness of 6.0 mm, section gap of 4.0 mm, repetition time (TR)/echo time (TE) of 3.02/1.51 ms, flip angle of 60° and temporal resolution of 33.22 ms. Parallel imaging was performed using the GRAPPA (generalized autocalibrating

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Each CMR examination was enhanced with 0.2 mmol kg21 body weight of gadopentetate dimeglumine (Magnevist®; Bayer Vital, Leverkusen, Germany). 10 min after contrast application, late enhancement images were acquired using a segmented T1 weighted inversion recovery turboFLASH sequence in identical long- and short-axis planes (TE, 4.38 ms; TR, 2 3 RR interval; flip angle, 25°; pixel size, 1.4 3 1.8 mm2; section thickness, 8 mm and section gap, 2 mm). After acquisition of a TI scout for each patient, TI was adjusted to optimize the nullification of normal myocardium. TI ranged between 260 and 320 ms and was increased by 10 ms approximately every minute during the acquisition to optimally “null” the normal myocardium. Cardiac MRI analysis Left ventricular (LV) ejection fraction, LV mass and ventricular volumes were measured with short-axis stack cine imaging, using semi-automated software (Argus v. 2.3; Siemens Medical Systems). All ventricular volumes were indexed for body surface area (BSA). Qualitative interpretation of CMR scans was performed based on the consensus between two experienced interpreters who were blinded to clinical details. Cine images were reviewed, including assessment of regional wall thickness and wall motion abnormalities. Fat-suppressed TIRM images were examined for areas of high signal intensity suggesting oedema and used for measuring the ratio of myocardial signal intensity to that of skeletal muscle. A ratio of .1.9 was considered to indicate a significant increase in signal intensity.14 Finally, late-gadolinium-enhancement (LGE) images were assessed for the presence of areas of no-reflow (microvascular obstruction) and enhancing areas, as well as their locations within the myocardial tissue (e.g. subendocardial, subepicardial, midwall or transmural) and their segment-wise distribution. Segmental analysis of the left ventricle was performed using the 17-segment model of the American Heart Association.15 Acute myocardial infarction was diagnosed if image analysis revealed subendocardial or transmural late enhancement in the distribution of a coronary artery, accompanied by oedema and a regional wall motion abnormality (hypo- or akinesia) in that territory, which were larger than the LGE area.12,16 Myocarditis was diagnosed in cases presenting with focal or diffuse areas of oedema not related to the territory of a coronary artery, along with LGE in at least one segment of the subepicardial or midventricular myocardial layers. In these cases, cine imaging revealed either a normal or only mildly reduced global systolic function and no apparent regional wall motion abnormalities.14 Takotsubo CM was diagnosed in patients showing dyskinetic myocardial segments that created a ballooning pattern on cine

Br J Radiol;88:20150025

BJR Received: 7 August 2013

Accepted: 14 April 2014

doi: 10.1259/bjr.20130496

Cite this article as: Gao B, Zhang H, Zhang S-D, Cheng X-Y, Zheng S-M, Sun Y-H, et al. Mammographic and clinicopathological features of triple-negative breast cancer. Br J Radiol 2014;87:20130496.

FULL PAPER

Mammographic and clinicopathological features of triple-negative breast cancer 1

B GAO, MD, 1H ZHANG, MM, 1S-D ZHANG, MD, 1X-Y CHENG, MM, 1S-M ZHENG, MB, 1Y-H SUN, MB, 2D-W ZHANG, MD, Y JIANG, MD and 1J-W TIAN, MD

3 1

Department of Radiology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China Department of Breast Surgical Oncology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China 3 Department of Pathology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China 2

Address correspondence to: Dr Bo Gao E-mail: gaobo72519@gmail.com

Bo Gao and Hui Zhang both contributed equally to this article.

Objective: Triple-negative breast cancer (TNBC) lacks effective treatment and has a poor prognosis. This study assessed mammographic findings and clinicopathological features of TNBC by comparing with non-TNBC in order to improve clinical diagnosis of TNBC. Methods: A total of 426 patients with pathologically confirmed breast cancer were retrospectively assigned into two groups, TNBC (n 5 54) and non-TNBC (n 5 372), and then analysed. Results: TNBC frequently showed a high histological grade, presented with a mass (79.6%) and was less frequently associated with focal asymmetric density (11.1%), microcalcifications (5.6%) and distortion (3.7%) on mammography. TNBC mammographic masses were most

frequently round/oval (58.1%) or lobular (30.2%) in shape and were less frequently irregular in shape (11.6%). Masses with circumscribed margins were the most frequent (37.2%), with microlobulated (25.6%) and obscured (16.3%) margins being commonly observed, but masses with spiculated margins were rare (9.3%). Conclusion: TNBC could have distinct mammographic and clinicopathological features compared with nonTNBC, and thus mammography may be useful in the diagnosis of TNBC. Advances in knowledge: This study demonstrated distinct mammographic and clinicopathological features to help in diagnosis of Chinese patients with TNBC.

Breast cancer is the most common malignancy observed in females. Histologically, breast cancer is a heterogeneous disease with different subtypes and pathology, treatment options and prognosis.1 Bryan et al2 for the first time in 2006 explicitly presented the definition of triple-negative breast cancers (TNBCs) based on the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Other studies using gene expression profiling were able to classify breast cancer into five subtypes.3,4 To date, TNBC is used frequently as a standard procedure to classify breast cancer patients for clinical care. TNBC is similar to the basal-like subtype, which is characterized by negative ER, PR and HER2 expression, and is associated with aggressive histology, poor prognosis and unresponsiveness to the endocrine therapies.5,6 Moreover, TNBC has been used as a surrogate marker for the basal-like breast cancer, and approximately 80–90% of TNBCs are basallike breast cancers.7 Younger females have a higher rate of basal or breast cancer susceptibility gene mutation-related

TNBC, whereas older females have a higher proportion of apocrine, normal-like and rare subtypes of TNBC, including neuroendocrine TNBC.8 Because only fewer speciﬁc targeting therapies and molecular therapies (such as endocrine or target therapy) are available than for other subtypes of breast cancer, the standard treatment for TNBC includes surgery combined with adjuvant chemotherapy and radiotherapy, but clinical outcome is poor.7,9 Thus, early detection of this subtype of breast cancer is vital to improve the survival of patients. Although TNBC has been studied extensively in clinical and pathological literature, there are few reports on the radiological characteristics of this subtype of breast cancer. To date, mammography is known to be a precise diagnostic technique with high sensitivity and speciﬁcity in the evaluation of breast lesions, and the current reference standard in breast cancer screening is mammography with the sensitivity to detect early-stage breast cancer. Therefore, this study evaluated the mammographic and clinicopathological

BJR

Full paper: TNBC mammographic and clinicopathological features

Table 1. Comparison of clinicopathological features of triple-negative breast cancer (TNBC) with non-TNBC

Features

TNBC, n 5 54 (%)

Non-TNBC, n 5 372 (%)

p-value

Age (years) Mean

48.9

49.8

Range

32–72

29–88

Mean

2.35

2.38

Range

0.6–4.0

0.8–6.6

Positive

22 (40.7)

138 (37.1)

Negative

32 (59.3)

234 (62.9)

IDC

42 (77.8)

290 (78.0)

All others

12 (22.2)

82 (22.0)

I/II

10 (23.8)

220 (75.9)

III

32 (76.2)

70 (24.1)

0.6550

Tumor size (cm) 0.9280

Axillary lymph node 0.6050

Pathological type 0.9760

Grade of IDC ,0.0001

IDC, invasive ductal carcinoma.

features of TNBC by comparing these features to those of nonTNBC in order to make a more precise diagnosis. METHODS AND MATERIALS Patients We retrospectively recruited a total of 426 females with invasive breast cancer who were treated in our institution (The Second Affiliated Hospital, Harbin Medical University, Harbin, China) between July 2011 and December 2012. They all accepted mammography before undergoing the surgery. After surgical resection of tumour lesions, all tissue samples were immunohistochemically stained for the expression of ER, PR and HER2, which divided them into two groups, TNBC (n 5 54) and non-TNBC (n 5 372) (i.e., having at least one of the three positive biologic markers). The mammographic and clinicopathological data for these patients were retrieved from their medical records using the Electronic Medical Record Search Engine and retrospectively reviewed and analysed according to TNBC and non-TNBC groups. This study was approved by our institutional review board. Informed consent was obtained from each patient included in the study, and ethical approval for this study was given by the Ethics Committee at The Second Affiliated Hospital, Harbin Medical University, Harbin, China. The study has been performed in accordance with the ethical standards. Diagnostic imaging Mammography had been performed for each patient using a digital technique Lorad Selenia unit (Hologic, Bedford, MA). Mammograms with mediolateral oblique and craniocaudal views were performed on each patient, and additional views were also performed if necessary. In all cases, mammograms were retrospectively reviewed by three experienced Mammography Quality Standards Act-certified breast radiologists with 5–12 years of breast imaging experience who had no knowledge about the clinical and

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pathological findings of the patients. Mammograms were evaluated according to the 4th edition of American College of Radiology Breast Imaging Reporting and Data System.10 Any discrepancy was re-reviewed by all three breast radiologists together to reach a conclusion. Breast density was rated as fatty, scattered fibroglandular, heterogeneously dense or dense. The mammographic findings were described as masses, masses with calcifications, only calcifications, focal asymmetric densities or architectural distortions; and masses were evaluated for size, shape and margin. Margins of a mass were reviewed for being circumscribed, obscured, microlobulated, indistinct and spiculated. Histological assessment of tissue specimens All resected tissue specimens were diagnosed histologically. Haematoxylin–eosin staining was performed in formalin-fixed, paraffin-embedded tissue sections for pathological diagnosis. The following histological parameters were analysed: histological type, histological grade and the presence of hormone receptors (status of ER, PR and HER2 was determined by immunohistochemical analysis as part of routine pathological assessment for clinical management). The status of each receptor was considered to be negative if the expression was ,10% and positive if the expression was $10%. The HER2 status was graded as 0, 11, 21 and 31. HER2 score of 31 was defined as positive, and 21 was checked by fluorescence in situ hybridization for its positivity. Breast cancers with negative ER, PR and HER2 staining were grouped as TNBC. Statistical analysis All analyses were performed using statistical software (SPSS® v. 19.0; SPSS Inc., Chicago, IL). Patient characteristics were tabulated by immunophenotype or described by their median and range, as appropriate. The x2 test or the Student’s t-test was used for the comparison between the groups. A p-value ,0.05 was considered statistically significant.

Br J Radiol;87:20130496

BJR Received: 25 October 2013

Accepted: 18 December 2013

doi: 10.1259/bjr.20130685

Cite this article as: Kakarougkas A, Jeggo PA. DNA DSB repair pathway choice: an orchestrated handover mechanism. Br J Radiol 2014;87:20130685.

RADIOBIOLOGY SPECIAL FEATURE: REVIEW ARTICLE

DNA DSB repair pathway choice: an orchestrated handover mechanism A KAKAROUGKAS, MSc, PhD, and P A JEGGO, PhD Genome Damage and Stability Centre, University of Sussex, Brighton, UK Address correspondence to: Professor Penny Jeggo E-mail: p.a.jeggo@sussex.ac.uk

ABSTRACT DNA double strand breaks (DSBs) are potential lethal lesions but can also lead to chromosome rearrangements, a step promoting carcinogenesis. DNA non-homologous end-joining (NHEJ) is the major DSB rejoining process and occurs in all cell cycle stages. Homologous recombination (HR) can additionally function to repair irradiation-induced two-ended DSBs in G2 phase. In mammalian cells, HR predominantly uses a sister chromatid as a template for DSB repair; thus HR functions only in late S/G2 phase. Here, we review current insight into the interplay between HR and NHEJ in G2 phase. We argue that NHEJ represents the first choice pathway, repairing approximately 80% of X-ray-induced DSBs with rapid kinetics. However, a subset of DSBs undergoes end resection and repair by HR. 53BP1 restricts resection, thereby promoting NHEJ. During the switch from NHEJ to HR, 53BP1 is repositioned to the periphery of enlarged irradiation-induced foci (IRIF) via a BRCA1-dependent process. K63-linked ubiquitin chains, which also form at IRIF, are also repositioned as well as receptor-associated protein 80 (RAP80), a ubiquitin binding protein. RAP80 repositioning requires POH1, a proteasome component. Thus, the interfacing barriers to HR, 53BP1 and RAP80 are relieved by POH1 and BRCA1, respectively. Removal of RAP80 from the IRIF core is required for loss of the ubiquitin chains and 53BP1, and for efficient replication protein A foci formation. We propose that NHEJ is used preferentially to HR because it is a compact process that does not necessitate extensive chromatin changes in the DSB vicinity.

The notion that DNA represents the hereditary component of the cell necessitates that it maintains stability. Yet, pioneering work by Thomas Lindahl revealed that DNA incurs substantial damage, including base and sugar damage, DNA–DNA and DNA-protein cross links, single strand breaks and double strand breaks (DSBs).1,2 Given such extensive damage, it became evident that cells must have efficient DNA repair mechanisms if the DNA sequence represents the stably inherited determinant of cellular phenotype, a notion strengthened by the finding that DNA repair defective mutants in lower organisms are genetically unstable.3 The evolutionary conservation of DNA repair pathways further supports a critical role in maintaining genetic stability. The study of model organisms has substantially contributed to our understanding of DNA repair mechanisms, particularly DNA DSB repair, which is our focus here. Such studies have shown that mutants in lower organisms deficient in homologous recombination (HR) are exquisitely radiosensitive owing to the important role of HR in repairing DNA DSBs, the major lethal lesion induced by radiation.4–8 By contrast, mammalian mutants deficient in HR show only modest radiosensitivity. Further, studies examining plasmid rejoining in mammalian cells and DNA integration

events revealed a distinct process, initially called illegitimate recombination, which does not require extensive homology.9,10 The concept of a non-homologous end-joining (NHEJ) pathway for DSB repair was further substantiated by the study of radiosensitive mammalian mutants and consolidated by the identification of NHEJ genes.8,11 Indeed, mammalian cell lines, mice and patients with marked radiosensitivity have proved to display deficiency in NHEJ rather than HR (excepting ataxia telangiectasia, arguably the most radiosensitive human disorder, which is predominantly proficient in both pathways). HR does function in mammalian cells, however, and can contribute to DSB repair. Having gained a deep understanding of NHEJ and HR in mammalian cells, we can now evaluate the pathway interplay, and why one pathway dominates. This will be the focus of this review. AN OVERVIEW OF NON-HOMOLOGOUS END-JOINING AND HOMOLOGOUS RECOMBINATION Both, NHEJ and HR, have been well reviewed; only a brief overview encompassing points relevant to the current topic will be given.12–16 NHEJ is initiated by the binding of the

Review article: DSB repair pathway choice

Figure 1. Non-homologous end-joining (NHEJ) and homologous recombination (HR) demand different degrees of chromatin remodelling. NHEJ is a compact process that most likely requires little change to the chromatin in the double strand break (DSB) vicinity. HR requires extensive resection, repositioning of damage response proteins and engagement of the sister chromatid. For simplicity, we have shown histone loss in the DSB vicinity. However, the steps in HR may not lead to full histone loss but could involve histone repositioning or modifications to histone proteins. There is extensive evidence that epigenetic changes to histones in the DSB vicinity occur during HR. DNA-PKcs, DNAprotein kinase catalytic subunit; RPA, replication protein A; XLF, XRCC4-like factor; XRCC4, X-ray cross complementing Group 4.

BJR

ends from nuclease digestion but does not impede ataxia telangiectasia mutated (ATM) activation or signalling.17 DNA-bound Ku recruits the DNA-protein kinase catalytic subunit (DNA-PKcs), generating the DNA-PK complex, which activates the activity of DNA-PK.18 This kinase activity predominantly regulates endprocessing and NHEJ through autophosphorylation and also facilitates recruitment of a ligation complex, which encompasses DNA ligase IV (LigIV), X-ray cross complementing Group 4 (XRCC4) and XRCC4-like factor/cernunnos.19 Additional proteins also contribute to end processing, including polynucleotide kinase 39 phosphatase.20 The structure-speciﬁc nuclease, Artemis, is also required for rejoining a subset of DNA ends, which appear to represent those that incur some level of resection, possibly owing to their increased complexity.21 Overall, NHEJ represents a compact process, with current evidence suggesting that only a single Ku molecule binds to each end (Figure 1).22 HR, by contrast, uses an undamaged template to restore any sequence information lost at the DSB site. The initiating step of HR is 59 to 39 end resection, generating a 39 ended singlestranded region.23 Resection can be subdivided into an initiation step involving CtIP/MRE11-RAD50-NBS1 (MRN) followed by a process that extends the length of resected DNA.23 The latter process will be the major focus here. Replication protein A (RPA) rapidly binds to the single stranded DNA (ssDNA) tail, preventing the formation of secondary structures. Subsequently, RPA is displaced by RAD51 via a Breast Cancer Associated Gene 2 (BRCA2)–dependent process.24 RAD51 loading promotes invasion onto the undamaged template and strand displacement, generating D-loop formation, which is necessary to generate a Holliday junction and a heteroduplex molecule (Figure 1). Repair ensues using the undamaged strand as a template, followed by ligation of the DNA ends. Frequently, there is a second Holliday junction formed. Finally, resolution of the Holliday junctions completes the process, giving either cross-over or non–cross-over products, depending on the direction of resolution.

Ku heterodimer to double stranded DNA ends, an exceptionally rapid and efﬁcient process, owing to the avid end-binding capacity of Ku and its high abundance. DNA-bound Ku protects

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DISTINCT BUT OVERLAPPING ROLES OF NON-HOMOLOGOUS END-JOINING AND HOMOLOGOUS RECOMBINATION Although mammalian cells are diploids, HR rarely uses the homologous chromosome as a template for DSB repair.25 Consequently, HR only functions in late S/G2 phase when a sister chromatid is available. One mechanism underlying this regulation of HR is the control of resection by cyclin-dependent kinases.26,27 Consequently, NHEJ is the major DSB repair pathway in G0/G1 phase cells. Conversely, HR exerts its major role in promoting recovery from replication fork stalling, where the lesion activating HR can be an ssDNA region or a one-ended DSB formed by a collapsed replication fork, as opposed to a two-ended DSB induced by agents such as ionizing radiation (IR).28 Indeed, NHEJ is not a suitable process for rejoining one-ended DSBs generated by replication fork collapse/stalling, as rejoining distant oneended DSBs can lead to genetic rearrangements. Despite these distinct roles, HR can function to repair two-ended DSBs in late S/G2 phase that arise following IR. Here, we consider the interface between NHEJ and HR at such two-ended DSBs in G2 phase. To avoid roles of HR during replication, we uniquely evaluate DSB repair in G2 cells using cell cycle markers to identify

Br J Radiol;87:20130685

BJR Received: 2 May 2014

Accepted: 23 July 2014

doi: 10.1259/bjr.20140325

Cite this article as: Sun J, Pichler P, Dowling J, Menk F, Stanwell P, Arm J, et al. MR simulation for prostate radiation therapy: effect of coil mounting position on image quality. Br J Radiol 2014;87:20140325.

SHORT COMMUNICATION

MR simulation for prostate radiation therapy: effect of coil mounting position on image quality 1

J SUN, MSc, 2P PICHLER, B.App.Sc (MRT), 3J DOWLING, PhD, 1F MENK, PhD, 4P STANWELL, PhD, 5J ARM, MSc and P B GREER, PhD

1,2 1

School of Mathematical and Physical Sciences, University of Newcastle, Newcastle, NSW, Australia Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, NSW, Australia 3 Commonwealth Scientific and Industrial Research Organisation (CSIRO) Australian e-Health Research Centre, Brisbane, QLD, Australia 4 School of Health Sciences, University of Newcastle, Newcastle, NSW, Australia 5 Hunter New England Health, Newcastle, NSW, Australia 2

Address correspondence to: Mr Jidi Sun E-mail: jidi.sun@uon.edu.au

Objective: To eliminate the effects of body deformation for MR-based prostate treatment planning, coil mounts are essential. In this study, we evaluated the effect of the coil set-up on image quality. Methods: A custom-designed pelvic-shaped phantom was scanned by systematically increasing the anterior body-tocoil (BTC) distance from 30 to 90 mm. The image quality near the organs of interest was determined in order to characterize the relationship between image quality and BTC distance at the critical organ structures. The half intensity reduction (HIR) was calculated to determine the sensitivity of each organ structure to the BTC distance change. Results: As the BTC distance increased, the uniformity reduced at 3% per millimetre. The HIR value indicated that the bladder signal is most sensitive to the change in BTC

distance. By maintaining a constant BTC distance set-up, the intensity uniformity was improved by 28% along the B0 directions. Conclusion: Positioning the MRI coil on mounts can reduce body deformation but adversely degrades the image quality. The magnitude of this effect has been quantified for prostate MR simulation scanning. The coil needs to be positioned not only with a minimal but also uniform BTC distance in order to maximize image quality. Advances in knowledge: A method to characterize the effect on image quality due to the use of coil mounts was demonstrated. Coil mounts whose height can be adjusted individually to keep BTC distance constant are necessary to maintain a uniform image across the entire field of view.

Compared with CT images, MR images have superior soft tissue contrast, which increases the organ delineation accuracy. There is growing interest in the use of MR as the sole imaging modality for radiation therapy planning, with the increasing installation of MR scanners in radiation therapy departments and the development of MR linac devices.1–3 However, several factors limit the use of MRI as the sole modality for radiotherapy treatment planning. These not only include spatial distortion4–6 and lack of electron density7–10 but also the anatomy variation due to differences in patient positioning set-up on MR scanner from the treatment position. Khoo et al11 proposed that in order to apply MR scans to the radiotherapy, patient set-up on the MR scanner table needs to reproduce the one on the treatment table. For current scanners with a ﬂat table top, patient positioning is mainly affected by the surface coil that is conventionally attached to the patient’s pelvis, deforming the anterior external body contour.

For the prostate scan, the anterior body deformation owing to coil compression can be eliminated by using a coil mount to lift the coil above the body. Kapanen et al12 implemented a home-made coil mount to hold the coil above the body. They assessed the effect of their coil mount on spatial distortion. To simulate a flat treatment table, McJury et al13 inserted a flat panel onto the scanner in order to eliminate the posterior body deformation. They showed that by inserting a flat couch to their curved table top, the signal-tonoise ratio (SNR) in an oil-filled phantom decreased by 14%.13 To our knowledge, no systematic study has been conducted on the effect on image quality of lifting the coil above the scanned body using coil mounts. It is important to understand what effect these new coil positioning devices have on image quality and how best to utilize these devices for MRbased treatment planning to obtain optimal image quality. This study aims to determine the effect on image quality of using commercial coil mounts to lift the surface coil above

Short communication: MR simulation for prostate radiation therapy: effect of coil mounting position on image quality

BJR

Figure 1. Schematic diagrams of the anthropomorphic phantom in transverse view (a). Larger diagram in (b) shows the sagittal view and smaller diagram shows the transverse view of grid-phantom. A photo of coil mounts (c). Two coil mount set-ups are shown in (d) and (e), horizontal set-up and parallel set-up, respectively, where the main magnetic field (B0) direction indicates the phantom set-up on scanner. A flat table was used in this study.

the pelvis for prostate radiation therapy MR scanning. The effect of both variation in body-to-coil (BTC) distance along the main magnetic ﬁeld (B0) direction and increase in BTC distance in the anteroposterior (AP) direction are systematically examined using specially constructed pelvic-shaped MR test phantoms. The ﬁndings will assist with clinical implementation of these devices for MR-based planning and inform future design of these devices. METHODS AND MATERIALS Phantom design Two phantoms were custom manufactured to the shape of a human pelvis, with the external surface made of polymethylmethacrylate. One of the phantoms is an anthropomorphic phantom (“anthro-phantom”) containing all the organs of interest in surrogate structures (Figure 1a). The location and size of these structures were based on average results from 39 patient CT scans by Lambert et al.10 The prostate and bladder structures inside the anthro-phantom are shaped by hollow

plastic spheres, with holes drilled through the surface allowing liquid to fill the structure. The rectum is a cylindrical pipe filled with air, while the head of the femur is a solid plastic sphere. This phantom was used to estimate the image quality change near region of interest (ROI) structures when the BTC distance varied. The second phantom (“grid-phantom”) has the same external body dimension but with 11 plastic grid sheets positioned approximately 20 mm apart and parallel to each other (Figure 1b). This grid-phantom was originally designed for quantifying the geometric distortion of a pelvic-sized MR image. In this study, the grid-phantom was used to evaluate the image quality variation caused by different coil positioning set-ups. Image profiles were sampled at the spaces between adjacent grid sheets to give continuous image quality variation. Both phantoms were filled with mineral oil instead of water in order to avoid the standing wave artefact in our 3-T scanner.

Figure 2. Intensity map of the sagittal image acquired with horizontal set-up (a) as shown in Figure 1d and parallel set-up (b) as shown in Figure 1e, and the pixel-by-pixel-based percentage intensity difference (c). The coil orientation is illustrated by the white line. The arrows indicate the region of most signal loss.

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Br J Radiol;87:20140325

BJR Received: 17 June 2014

Accepted: 13 August 2014

doi: 10.1259/bjr.20140428

Cite this article as: Chopra S, Patidar A, Dora T, Moirangthem N, Paul SN, Engineer R, et al. Vaginal displacement during course of adjuvant radiation for cervical cancer: results from a prospective IG-IMRT study. Br J Radiol 2014;87:20140428.

FULL PAPER

Vaginal displacement during course of adjuvant radiation for cervical cancer: results from a prospective IG-IMRT study 1

S CHOPRA, MD, DNB, 2A PATIDAR, MD, 1T DORA, MD, 1N MOIRANGTHEM, DRP, 1S N PAUL, DRP, 2R ENGINEER, DNB, U MAHANTSHETTY, MD, DNB and 2S K SHRIVASTAVA, MD, DNB

2 1

Department of Radiation Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Mumbai, Maharashtra, India Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Address correspondence to: Dr Supriya Chopra E-mail: schopra@actrec.gov.in

Objective: To compare internal target volume (ITV) generated using population-based displacements (ITV_study) with empty and full bladder scan fusion (ITV_EBFB) for organ-at-risk (OAR) doses during adjuvant intensitymodulated radiation therapy (IMRT) for cervical cancer. Methods: From January 2011 to October 2012, patients undergoing IMRT were included. CT simulation was carried out after inserting vault markers. Planning target volume (PTV)_EBFB received 50 Gy per 25 fractions. Pre-treatment megavoltage CT (MVCT) was performed. MVCTs were registered using bony landmarks with Day 1 MVCT. Displacement of the centre of mass of markers was measured along each axis. Directional ITV was calculated using mean 6 2 standard deviations (SDs) (ITV_study). Replanning was performed using PTV study, and OAR doses were compared with PTV_EBFB using Wilcoxon test.

Results: A total of 348/386 data sets were evaluable for 16 patients. The median vaginal displacement was 1.2 mm (SD, 1.3 mm), 4.0 mm (SD, 3.5 mm) and 2.8 mm (SD, 3.3 mm) in the mediolateral, superoinferior and anteroposterior directions, respectively. The ITV margins were 4.1, 10.3 and 10.6 mm. ITV_study and ITV_EBFB were 115.2 cm3 (87.7–152.2 cm3) and 151 cm3 (95.7–277.1 cm3) (p , 0.0001), respectively. PTV_study and PTV_EBFB were 814 and 881 cm3 (p , 0.0001), respectively. Median doses to the bladder were lower with the PTV_study (46.2 Gy vs 43.2 Gy; p 5 0.0001), and a similar trend was observed in the volume of the small bowel receiving 40 Gy (68.2 vs 60.1 cm3; p 5 0.09). Conclusion: Population-based PTV margins can lead to reduction in OAR doses. Advances in knowledge: Population-based ITV may reduce OAR doses while executing adjuvant IMRT for cervical cancer.

Adjuvant pelvic radiation for cervical and endometrial cancers is recommended in patients with adverse histopathological features following surgery.1,2 Although it improves outcomes, it is associated with increased acute and late bowel morbidity.1,2 Recently published results of the Radiation Therapy Oncology Group (RTOG) Phase II study demonstrate that the use of pelvic intensitymodulated radiation therapy (IMRT) is associated with reduced treatment-related acute and short-term gastrointestinal (GI) toxicity, and this can be achieved without worsening disease control.3 However, implementing IMRT may be challenging owing to the unpredictable nature of vaginal displacements during the course of external radiation. Therefore, the RTOG recommends that for planning IMRT, both empty and full bladder (EBFB) scans should be obtained for localizing residual vagina and for generating the internal target volume (ITV).4 These recommendations are being followed by two ongoing Phase III randomized

controlled trials that aim at reducing acute and late bowel toxicity of adjuvant pelvic radiation.5,6 Although this strategy may ensure that all extreme displacements arising out of variations in bladder ﬁlling are accounted for, this may result in increased planning target volume (PTV) and thereby increased dose to adjacent organs at risk (OAR). Strong correlation has been reported between the dose received by the bowel and late bowel morbidity after adjuvant pelvic radiation for cervical cancer.7 The present study was initiated with an aim of evaluating vaginal displacement for the post-hysterectomy cohort and to investigate if population-based ITV could reduce dose to OARs. METHODS AND MATERIALS The present study was conducted on megavoltage CT (MVCT) data sets of patients with cervical cancer scheduled to receive post-operative adjuvant image-guided (IG)-IMRT

Full paper: Vaginal displacement during adjuvant radiation

with or without chemotherapy and randomized to the tomotherapy arm within the context of ongoing institutional ethics committee-approved Phase III randomized controlled trial.5 The study included patients who had undergone simple or Wertheim’s hysterectomy and required adjuvant treatment owing to adverse pathological risk factors or suboptimal nodal dissection. Patients with gross residual local or nodal disease, para-aortic disease, history of multiple abdominal surgeries or medical conditions placing patients at high risk of baseline GI dysfunction were excluded. Fiducial marker placement All patients underwent silver marker placement in the vaginal apex prior to simulation. Patients were positioned in lithotomy position, and the vaginal apex was identified through per speculum examination. Silver markers (one each) were inserted in the left and right vaginal apex. All patients received 3 days of antibiotics (500 mg of ciprofloxacin twice daily) following marker insertion. CT simulation Patients were instructed to report for CT simulation after evacuating bowel contents. No specific dietary modification or stool softeners were prescribed. Radiation planning scans were obtained with EBFB to encompass unpredictable bladder filling.4,8 For the EB scan, patients were instructed to void the bladder. Patients were positioned supine with arms above their heads. Three radio-opaque fiducial markers were placed at laser intersection points on the lower abdomen and a radio-opaque marker was placed at the vaginal introitus while obtaining the scan. CT scan was obtained from L2–3 junction to mid-thigh at an interslice thickness of 3 mm. After the EB scan, patients were instructed to consume 500 ml of water and wait for 30 min. Patients were repositioned and imaged after injecting intravenous contrast at approximately 40 min after consuming water. Both the image data sets were exported to the Oncentra® (Nucleotron, Stockholm, Sweden) treatment planning system v. 4.1 for target volume delineation. Target delineation and treatment details Rigid bony registration was performed for FB and EB data sets. While FB scan formed the primary data set, the EB scan formed the secondary data set. Within these data sets, the vault and introitus markers were used to define the length of the vagina. For each of the data sets, the upper half of the vagina was contoured. As the vesical peritoneum is surgically violated during hysterectomy, the vaginal contour was expanded anteriorly by 1.0–1.5 cm and superiorly by 1.0 cm, posteriorly till the mesorectal fascia and laterally till the pelvic muscles, to generate the clinical target volume EBFB (CTV-EB and CTV-FB). Contours were not edited from distensible or mobile OARs. Boolean operation was used to perform a union of CTV-FB and EB to generate the ITV (ITV-EBFB). Another 7-mm margin was added to ITV to generate PTV for the primary tumour bed. Nodal delineation was carried out using standard guidelines.8 Nodal CTV was expanded by 5 mm to generate nodal PTV. Boolean operation was used to perform a union of nodal and primary PTV to generate the final PTV (or PTV EBFB). The OARs except the bowel were delineated using standard guidelines.9 The bowel delineation included contouring individual small and large

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bowel loops. All patients received 50 Gy per 25 fractions over 5 weeks with or without concurrent chemotherapy. This was followed by vaginal high-dose-rate brachytherapy (12 Gy per two fractions, each fraction delivered 1 week apart). Image guidance during treatment Patients were instructed to report after evacuating the bowel and were instructed to repeat the FB regimen, as at the time of the planning scan for daily treatment. A daily pre-treatment MVCT was performed. The daily imaging volume was selected from L4 to the lower extent of the pelvis such that the entire planned target volume was scanned, with some additional margin. The “normal” setting on tomotherapy (4-mm slice thickness) was used for MVCT scanning. Automated registration of the planning kilovoltage CT and daily MVCT images was performed using rigid bony registration. All translations and rotations were recorded but only translational shifts and roll were applied for patient position correction. The pitch and yaw rotations in the patient set-up were recorded but not applied. The treatment was delivered, and a post-treatment MVCT scan was also performed. Evaluation of vaginal displacement MVCT images were transferred to the FOCAL® SIM v. 4.3.3 (CMS Medical Systems, Oldham, UK) workstation. The Day 1 MVCT images served as baseline images for evaluation of interfraction vaginal displacement. All subsequent MVCT images were co-registered with Day 1 MVCT using rigid bony registration such that residual displacements of vaginal markers represent internal organ motion. If the vaginal marker was seen in only one MVCT slice, then that particular slice was considered as the reference slice. If, however, the vaginal marker was seen in two slices, then consistently, the caudal slice was used for the purpose of analysis. If two markers were seen on the same slice, then only one marker (right sided) was used to calculate the displacement. If no vaginal marker was identiﬁed, then that particular CT data set was excluded from analysis. Vaginal marker in an axial slice was visible as a point or elliptical radioopaque structure. A three-dimensional (3D) localizer point was placed over the visualized marker to obtain the 3D location or centre of marker (COM). For each fraction, the displacement of this COM from the baseline was recorded. The right, superior and anterior displacements were coded as positive displacements and the left, posterior and inferior displacements as negative displacements from the baseline or Day 1 MVCT. While the medio-lateral (ML) and anteroposterior (AP) displacements could be recorded within an accuracy of ,1 mm, the evaluation of the craniocaudal (CC) displacement was limited by the MVCT slice thickness (i.e. 4 mm). For each patient, we calculated the mean and standard deviation (SD) of displacement in the ML, AP and CC directions. ITV margins were calculated using various published margin expansion formulae.10,11 In addition, ITV was generated using 95% conﬁdence intervals (95% CI) around the directional mean (mean 6 2SD). This directional expansion was applied to CTV FB and was named as ITV_study for the purpose of this investigation. Planning target volume and organ-at-risk doses Using ITV_study and ITV_EBFB, an isotropic expansion of another 7 mm was applied to generate PTV_study and

Br J Radiol;87:20140428

Join the growing community You may have picked up this copy of Best of BJR from our stand at an event in the UK, Europe or even further afield. This year we are actively attending more events so we can meet radiologists, physicists and radiographers from across the world and we warmly invite you to join our community. We now have an international membership option and joining is easy. We offer discounts to members of some societies, so please ask us if yours qualifies. Don’t forget, joining the BIR gives reduced rate membership of other societies too, such as the Royal Society of Medicine. Please visit our website www.bir.org.uk for more details. BJR| case reports As BIR membership grows, I’m thrilled to tell you about some exciting developments. BJR is the first radiological journal in the world but we now have one of the newest too. BJR| case reports is an international open access journal of radiology, radiation oncology and all related sciences. We have already published some articles and welcome your submissions for which, throughout 2015, there is no article publication charge. Free webinars Education is at the heart of all we do at the BIR so we are proud to add webinars to our learning portfolio. See and interact with expert physicists, radiologists and radiographers from around the world, all with the ethos of multidisciplinary working. For a limited time these webinars are completely free, so do take part. There’s never been a better time to join in with the BIR community and we look forward to welcoming you. Jacqueline Fowler CEO | The British Institute of Radiology

120 years of radiology history at your fingertips All BIR members have FREE access to BJR, our flagship journal. Members have access to articles written just months after the discovery of X-rays through to the latest research and reviews. The BIR has digitized the whole BJR back catalogue, including the journals that make up the origin of the BJR including Archives of the Roentgen Ray and The Journal of the Röntgen Society. With more than 28,000 items in the archive, including the first published picture of a whole body X-ray, your reading options are virtually endless. The archives are a fascinating journey through the history of radiology from the first experiments with the “new photography” through to the development of CT, MRI and onto the 3D modalities of the digital age. Read articles from Nobel Laureates Joseph Rotblat, Sir Peter Mansfield, Sir Godfrey Hounsfield, George de Hevesy, Sir William Bragg and Sir Lawrence Bragg. Organisations can purchase our digital archive package called BJR|from the beginning. No subscription, pay once and access forever. Contact publication.sales@bir.org.uk for a quote.

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Books

The BIR has been publishing books for over 60 years and is the only dedicated radiology publisher in the world. Our books are written by world renowned doctors and scientists. You can purchase our books from our online bookshop, and don’t forget that BIR members get 25% off all books. View our bookshop at www.bir.org.uk/publications.

A jobs board just for you Medical imaging, clinical oncology, medical physicist and radiography posts are just some of the jobs you will find on the BIR jobs board. You can search for relevant jobs and set up a job alert so you are notified when a job matching your skills is posted. Why not upload your CV so employers can find you? Find the jobs board from our home page, www.bir.org.uk. If you are advertising a post, we can offer special rates to BIR individual and corporate members. Contact advertising@bir.org.uk.

Free human anatomy software Special rates for new ualifiers If you are about to take up a consultant post or qualify as a radiographer you may be entitled to a special member rate if you have previously been a trainee or student member of the BIR.

All BIR members now have FREE access to anatomy.tv from Primal Pictures, the world’s most medically accurate and detailed 3D graphic rendering of human anatomy. Use this renowned anatomy software to teach, learn and practise. Ideal for practising clinicians, lecturers and students.

Trainees pay just £100 as a consultant and radiographers pay just £35 for their first three years of full membership. To find out more www.bir.org.uk/join-us.

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Shocked and inspired: reflections on radiology in Tanzania Winners of the 2013 BIR/Philips Student Travel Bursary, Faye Morrissey and Saima Dalvi, share their eye-opening experience in the radiology department of a hospital in Tanzania. “In the third year of our Diagnostic Radiography degree at the University of Derby we had the opportunity to undertake a 3-week elective placement. We decided to travel to Arusha in Tanzania to work in the radiology department of a regional government hospital. We chose this elective as we felt it was important to experience healthcare delivery in a developing country. We were delighted and very grateful when we won the BIR/Philips Student Bursary which helped us make the experience possible. The placement itself was an incredible eye opener. Practice in Tanzania is so vastly different to the UK. We were challenged both mentally and emotionally each day. Our radiography skills were pushed to the limit as we were expected to provide quality diagnostic images with technology we had never even experienced before. We strongly believe that going back to basics in this way has made us better radiographers and changed our perspective of what it means to be a professional in the healthcare setting. For example, when we arrived in the imaging department we were shocked to discover that the hospital had run out of X-ray film. For 2 weeks patients were denied imaging. Staff were forced to send patients to private hospitals where examinations cost six times as much. The large majority of patients we encountered had struggled to afford an X-ray at the government hospital we visited therefore the chances of them accessing private healthcare were extremely slim. Being surrounded by extreme poverty and the difficulties it brings, we now truly appreciate what it means to live in a country with government-funded healthcare and education. We quickly realised that trying to change practice would have been both inappropriate and unachievable. Overall, the experience provided an enormous appreciation for the radiography training we have received in the UK.”

BIR prize winners announced Stand apart from the crowd and enter a BIR award!

The BIR/Philips Trainee Award for Excellence is an award for BIR trainee members which this year was won by Dr Mark Rodrigues and team from the Royal Infirmary of Edinburgh. The award aims to encourage trainees to share and expand their learning by showcasing good practice in multidisciplinary working. The cash prize of £750 and a certificate are awarded for the best educational resource on the subject of theory and practice of radiology or radiation oncology. Applications will be accepted from groups of two or more trainees. The BIR/Philips Student Travel Bursary offers £250 to a student, of any discipline, to attend a radiology or radiation oncology educational event. Read a winner’s story above.

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BJR themed issues

Highlighting current hot topics and emerging areas of research. We publish up to three special features a year and a list of the previous themed issues can be found on the BJR website. Our 2015 special features are: Advances in radiotherapy: individualization, imaging, combined and new technologies, guest edited by Professor Mechthild Krause (University Hospital C.G. Carus, Germany). Topics covered include personalisation and biomarkers, functional imaging, SABR/IGRT/IMRT, motional management, proton therapy, radionuclides, radiation protection, chemoradiotherapy, radiotherapy for benign disease, and toxicity. Nanoparticles, guest edited by Kevin Prise (Queen’s University Belfast, UK) and inspired by the popularity of BJR articles on nanoparticles. Covering a broad range of research and applications of nanotechnology to the imaging sciences from radiation enhancers, pharmacokinetics of nanoparticles for radiomedicine, imaging nanoparticles in vivo, as well as nanoparticles and radionuclide therapy. Interventional musculoskeletal procedures, guest edited by Professor Giuseppe Guglielmi (University of Foggia, Italy) and Professor Carlo Masciocchi (Università degli Studi dell’Aquila, Italy), providing a comprehensive overview on state-of-the-art interventional musculoskeletal procedures, best practice and emerging trends in the field.

Sharing knowledge with Whether it’s by choice or to comply with funding mandates, our open access initiative BIR|Open, allows authors the opportunity to make their work free to access when published. We believe in the importance of research and education, and this is one of the ways we promote the sharing of knowledge and understanding. Initially offered as a optional extra for authors publishing in BJR and DMFR, we have taken our commitment to the sharing of knowledge a step further with our open access eBook, The Safe Use of Ultrasound in Medical Diagnosis, and our new journal, BJR| case reports.

Publishing for other societies As well as publishing our own range of journals and books, the BIR publishes for other societies. We publish DentoMaxilloFacial Radiology (DMFR) on behalf of the International Association of Dentomaxillofacial Radiology (IADMFR) and have published a number of books in conjunction with our sister radiology societies including The Safe Use of Ultrasound in Medical Diagnosis pictured above. We offer a personalized and professional service to those who publish with us. For example, we have been working hard developing DMFR over the last couple of years. We introduced continuous publication and reduced acceptance to final publication times to just 4 weeks. We also added BIR|Open and a newlook modern DMFR website for enhanced and more user-friendly content delivery. Looking for a publisher for your journal, book or conference proceedings? Contact publications@bir.org.uk.

www.bir.org.uk

Cigarette cards and cryptographs, William Coolidge and Marie Curie Just some of the names and objects from our “Radiology and WW1: Objects and People” film launched to commemorate the centenary anniversary of the start of World War I. Hear Dr Adrian Thomas, BIR Honorary Librarian and radiology history expert, in a fascinating interview with BIR past President Professor Andrew Jones. View it on our website www.bir.org.uk/about-us/history/radiology-and-wwi.

BJR cover competition winner! This year’s winning cover competition picture is one for the GI fans out there. Our 2015 cover features an image by Dr Rohit Bhoil, “Virtual colonoscopy”, an endoluminal view of the colon. It’s never too early to start looking for an eye-catching image to enter.

Those BJR travelbugs certainly are well travelled... We have given away over 5,000 of our BJR family of logo bugs over the last few years. Some of you have taken yours to some far flung destinations. Share your BJR logo bug pictures using #BJRTravelbug. Follow @BJR_Radiology on Twitter and see how far they’ve travelled!

The competition for the 2016 cover opens on 1 August 2015 and closes on 30 October 2015.

New partnerships The BIR is delighted to have joined the Alliance for Pediatric Imaging, also known as Image Gently. The BIR supports the Alliance’s objective of raising awareness in the imaging community of the need to adjust radiation dose when imaging children and the ultimate goal of changing practice.

www.bir.org.uk

Dr David Wilson, President of the BIR said, “We are committed to safety in radiation dose and we are delighted to support this organisation which does much so much to spread the word amongst parents and healthcare providers.”

Free webinars!

Our webinars are free for a limited time, so don’t miss this chance to enjoy CPD accredited education from the comfort of your own office at absolutely no cost! If you miss a live webinar, don’t despair! They are available on demand and by submitting a completed self-reflection form, you can still obtain your CPD credits. See talks by Professor Erika Denton (pictured) on imaging service delivery from the NHS England perspective, Mr Andy Rogers on management of patient skin dose and many more covering a range of multidiciplinary topics. View our forthcoming and on-demand webinars at www.bir.org.uk/education-andevents/bir-webinars.

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case BJR|reports

eISSN: 2055-7159

Rigorous peer review | Rapid publication | Open access

An international open access, case report journal of radiology, radiation oncology and all related sciences published by the BIR BJR|case reports provides unrestricted access to interesting case reports, case reviews and technical notes with educational value to clinicians and researchers as part of our open access initiative, BIR|Open. Articles undergo the same rigorous peer review and uphold the same high standards as BJR, the BIR’s flagship journal and published online as soon as the article is ready.

Editor-in-chief Professor Giuseppe Guglielmi University of Foggia and Casa Sollievo Hospital Scientific Institute Italy

Journal launch at UKRC 2014, L to R: Dr Leonardo Vedolin, Dr Maria Antonietta Mazzei, Dr Katja Pinker, Prof. Giuseppe Guglielmi, Prof. Rick van Rijn, Dr Valeria Panebianco, Dr Christoforos Stoupis.

Senior editors Dr Ausami Abbas, Canada

Dr Anastasia Fotiadou, United Kingdom

Dr Katja Pinker, United States

Dr Lorenzo Biassoni, United Kingdom

Dr Tim Lautenschläger, United States

Dr Christoforos Stoupis, Switzerland

Prof. John Damilakis, Greece

Dr Maria Antonietta Mazzei, Italy

Prof. Rick van Rijn, The Netherlands

Dr Andrew Forauer, United States

Dr Valeria Panebianco, Italy

Dr Leonardo Vedolin, Brazil

Read All BJR|case reports articles are published under an open access licence and will always be free for anyone to access and re-use the content, with the correct credit for the original work. For the lastest issue go to www.birpublications.org/bjrcr.

Submit BJR|case reports welcomes submissions of case reports, case reviews and technical notes in all areas of radiology and the related sciences. All article publication charges are waived until the end of 2015 and we will be applying for inclusion in indexing services such as PubMed/MEDLINE as soon as the required amount of content has been published. Instructions for authors: www.birpublications.org/page/ifa/bjrcr Submit your paper online: www.editorialmanager.com/bjrcr

Contact BJR|case reports Submissions and peer-review enquiries: bjrcroffice@bir.org.uk Manuscripts accepted for publication enquiries: bjrcrproduction@bir.org.uk For all other enquiries: publications@bir.org.uk

birpublications.org/bjrcr

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