The reconstruction of cone-beam CT (CBCT) images, as widely used in radiation treatment planning, is a complex mathematical problem. Extensive research into reconstruc-tion algorithms has resulted in the creation of new, improved recon-struction algorithms every year. But despite this, end-users mainly employ the simplest algorithm – FDK – which works well for high-quality, full-projection data, but performs poorly in less ideal scenarios.

Studies have shown that iterative algorithms outperform FDK, but their implementation is hindered by large demands on memory and computation time. “We noticed a big gap between image reconstruction research and what is actually used in medical applications,” explained Manuchehr Soleimani from the University of Bath. “Two important factors are that these algorithms are significantly slower than the stand-ard FDK and that they are not acces-sible enough to non-experts.”

To bridge this gap, Soleimani and colleagues from the University of Bath and CERN have developed the TIGRE (tomographic iterative GPU-based reconstruction) toolbox. Featuring a wide range of iterative algorithms, the toolbox is designed to be fast and easy to use, both for algorithm developers and medical end-users (Biomed. Phys. Eng. Express 2 055010).

What’s in the box?The main building blocks of any iterative algorithm are the projec-tion and back-projection opera-tors. To address the computation demands of iterative approaches, the researchers used CUDA to opti-mize these two blocks for graphics processing units (GPUs), thereby

exploiting the massive paralleliza-tion afforded by GPUs. “The only way of making the code fast is by programming specific GPU code in very low-level programming lan-guages, such as CUDA,” explained first author Ander Biguri. “However, these are hard to learn to use and programming in them is tedious.”

So to make TIGRE more user-friendly, the researchers coded the actual algorithms in MATLAB, a high-level, programming language that’s easy to use and intuitive. “We combined the best of both, by accel-erating the most computer-expen-sive blocks in the GPU, but allowing users to just use them in MATLAB,” added Biguri.

The toolbox currently incorporates algorithms from four reconstruction families: the standard FDK algo-rithm; a range of algorithms from the SART-type family (SIRT, OS-SART and SART); CGLS from the Krylov subspace family; and the total vari-ation regularization methods ASD-POCS, OSC-TV, B-POCS-TV-β and SART-TV. By incorporating these “black box” algorithms, TIGRE makes it easy for researchers who are only interested in image quality to test dif-ferent algorithms, without requiring knowledge of how they work.

To illustrate the functionality of their toolbox, the authors presented two reconstr uction examples. First, they used three algorithms to reconstruct data obtained from the RANDO head phantom. Image cross-sections showed that FDK resulted in noise across the entire image and significant strike arte-facts. The iterative methods OS-SART and CGLS created smoother images, removed most artefacts and exhibited clearer separation between tissues. Processing times were 20 s,

46 min 30 s (40 s per iteration) and 4 min 41 s (20 s per iteration) for FDK, OS-SART and CGLS, respectively.

The possibility of reconstructing full 3D images using a reduced radia-tion dose is an important feature for CBCT development, particularly for radiotherapy applications where the patient may require imaging at each treatment fraction. In a second test, the team used FDK, OS-SART and ASD-POCS to reconstruct data from just 20 projections of a 3D Shepp–Logan phantom. In this extreme case, the increased performance of the minimization algorithms over FDK was evident, especially for ASD-POCS. Processing times were all below one minute.

Look to the futureThe researchers note that while the toolbox enables image reconstruc-tion with complex iterative algo-rithms in just a few minutes, further improvements are possible. One possibility would be to implement the algorithms in C++/CUDA –

which would improve computation time by up to 50%, but make it harder to add new algorithms. The authors consider that the advantages of a high-level programming language for new algorithms outweigh the benefits of doubling the speed, which is already reasonably good.

“We decided that the toolbox is reasonably fast now, almost as fast as it can be, and we can already reconstruct quite large images in a good time scale,” explained Big-uri. “So to improve the toolbox, we will focus on incorporating novel algorithms and methods that could help improve images for radio-therapy treatment planning. Our own particular interests are new algorithms for motion correction and few-projection tomography for accurate tumour location and imag-ing dose reduction.”

The TIGRE code, which was recently released to the community, is open source, allowing anyone to download, test, modify and improve it. “Several research groups have shown interest in TIGRE and some of them are already trying it,” Soleim-ani told medicalphysicsweb. “Feedback has been quite positive, and it seems that the wide range of algorithms included in TIGRE and its geometric flexibility is very interesting to some research groups.”

“Hopefully, people will engage with TIGRE,” he added. “And we will have improvements coming not only from the current TIGRE team – the Engineering Tomography Lab at the University of Bath, and Steven Hancock and Manjit Dosanjh from CERN – but also from all of the research community.”

Tami Freeman is editor of medicalphysicsweb.

“We noticed a big gap between image reconstruction research and what is actually used in medical applications.”

Lower dose: 30-projection phantom image reconstructed using (left to right) FDK, and the iterative algorithms OSC-TV, ASD-POCS and SART-TV.

In association with the journal Physics in Medicine & Biology Issue 3, 2016

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Advances in CBCT reconstructionTIGRE toolbox brings advanced CBCT reconstruction algorithms to radiotherapy planning.

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This issue, distributed at the ASTRO Annual Meeting in Boston, MA, brings you some examples of our recent online content. If you like what you see, check out the website to read more in-depth news and research articles. Or register for free as a member – simply visit medicalphysicsweb.org or visit us at booth #12092. Tami FreemanEditor, medicalphysicsweb

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Radiation oncology special edition

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Lung SBRT is feasible with MR-linacBy accounting for the presence of the magnetic field during treatment planning, it is possible to deliver clinically acceptable MR-guided lung stereotactic body radiotherapy (SBRT) treatments, report a team of researchers from the UK (Radiother. Oncol. 119 461). Allaying concerns over potential dose distortions, this result may pave the way towards improved radiotherapy treatments.

D ur i ng radiot herapy, lung tumours can undergo both defor-mations and movements of up to a few centimetres. If not accounted for, these shifts can lead to under-dosage of the target tumour and unwanted extra irradiation of the surrounding tissues. Given this, the integration of MR imaging with radiation treatments is an attractive prospect: allowing for the real-time acquisition of images, with excellent soft-tissue contrast, during patient treatment. When combined with multi-leaf collimator (MLC) tumour tracking, such images can be used to dynamically re-optimize treat-ment plans to account for observed changes in patient anatomy.

Distortion concernsDespite the potential benefits of this approach, however, concerns have been raised that radiotherapy doses delivered during MR scanning might become distorted. Within the scanner’s magnetic field, the Lor-entz force could alter the path of the secondary electrons responsible for the absorbed dose, causing them to travel along spiral trajectories, rather than in straight lines.

The treatment of lung tumours may be particularly affected by this, as the distorting phenomena would

be pronounced at air–tissue inter-faces, explains paper author Martin Menten, a medical physicist at the

Institute of Cancer Research. “When entering low-density material, such as lung tissue or air, the range of travel of these electrons often increases sufficiently such that they can return to their surface of entrance,” he says. “This so-called electron return effect causes local dose ‘hot spots’ at air-tis-sue interfaces.”

A variety of strategies have been proposed to address these per-turbations – such as using altered magnetic-field and photon-beam geometries, limiting the strength of the magnetic field, or accounting for the distortion during treatment plan optimization. Exploring the latter solution in their new study, Menten and colleagues simulated lung SBRT with an MR-linac, for nine patients. For each patient, simula-tions were run both with and with-out real-time MLC tumour tracking, as well as within a 1.5 T magnetic field and without.

When radiotherapy treatment was undertaken in the magnetic field, the researchers observed slight dose dis-tortions at the air–tissue interface – resulting, for example, in a 1.4 Gy average increase in dosage to 2% of the skin.

At the same time, the research-ers found that the magnetic field did not limit the ability of MLC tumour tracking to decrease the dose exposure of healthy tissues while still maintaining the target dose to the tumour.

Bryan Bednarz – a medical physi-cist at the University of Wisconsin-Madison who was not involved in this study – comments that the clini-

cal adoption of disruptive technolo-gies like MR-guided radiotherapy is far from trivial. “In the case of MR-linacs, magnetic fields introduce new challenges during treatment plan-ning, which need to be investigated to ensure the patient is treated in the safest possible manner,” he says.

“While the proof of the pudding is in the eating, this work helps con-vince us that some of these challenges are manageable and clinical gains from this technology are plausible.”

Tremendous potential“It’s exciting to see work progress-ing on real-time MR-guided radia-tion therapy,” adds Charles Kirkby, a medical physicist at the Univer-sity of Calgary who was also not involved in this study. “Coupled with the image quality available through MRI, there is tremendous potential for this technology to improve the quality of SBRT for the treatment of lung tumours.”

With this study complete, the researchers are continuing to work on implementing real-time adap-tive radiotherapy on a MR-linac platform. “We anticipate that we can adapt our in-house MLC tracking control software for the MR-linac at our institution in 2017,” Menten told medicalphysicsweb. The team is pres-ently developing specialized MR-sequences and image-processing techniques to enable localization of tumour and healthy tissues during dose deliveries.

Ian Randall is a science writer based in New Zealand.

Dose simulation: CT slice of a lung cancer patient overlaid with (A) the simulated dose with a 1.5 T magnetic field present, (B) the delivered dose without a magnetic field, and (C) the difference between the two.

In a bid to improve treatment out-comes, researchers are increasingly investigating ways to tailor radio-therapy to individual tumour biol-ogy. In new work, a US centre has used PET hypoxia imaging to identify head-and-neck cancer patients with normoxic, radio-responsive disease and reduce the dose they receive.

Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York carried out the pilot study in 33 chemoradiotherapy patients with human papilloma virus posi-tive (HPV+) oropharyngeal cancer. The study is part of a larger trial assessing PET hypoxia imaging in head-and-neck patients.

“Our data so far show that radia-tion de-escalation does not com-promise tumour control in HPV+ disease,” said first-author Nancy Lee, a radiation oncologist at MSKCC. The study provides promising pre-liminary evidence that dose de-

escalation guided by PET imaging of hypoxia is safe and feasible (Int. J. Radiat. Onc. Biol. Phys. doi: 10.1016/j.ijrobp.2016.04.027).

Lee and colleagues identified HPV+ patients as good candidates for de-escalation because the group has a significantly better prognosis than patients with other types of oropharyngeal cancer, with overall survival close to 90%. The research-ers took a conservative approach, only de-escalating the dose to lymph nodes with gross disease in carefully selected patients, down from 70 to 60 Gy. The researchers identified suitable individuals – those with normoxic, radio-responsive disease – using dynamic F-18 FMISO scans. Imaging was carried out before patients started treatment, then after one week of treatment in those where hypoxia had been detected.

“Piecewise PET image acquisitions were performed over a three hour period,” explained senior author John Humm, head of nuclear-med-icine physics at MSKCC. “We used tracer kinetic modelling to estimate the rate of irreversible F-18 FMISO radiotracer trapping, the ratio of F-18 FMISO uptake [in the tumour] relative to background tissue and also just visual interpretation.” The rate of irreversible trapping of F-18 FMISO is proportional to the degree

of hypoxia in the tumour tissue. Patients were de-escalated if they had no evidence of hypoxia on their pre-treatment images, or if PET did show hypoxia, it had to be absent in the subsequent scan.

Hypoxic tumour cells were detected in all individuals before they started treatment. After a week of treatment, 10 patients out of the 29 who had repeat scans had normoxic nodes and were de-escalated. In sev-eral cases, the dynamic PET findings contradicted tumour:background uptake ratios and qualitative image appearances. Here, the authors classified the disease as normoxic or hypoxic by consensus. They are investigating the discrepancies more closely in a follow-up study. One de-escalated patient had persistent nodal disease following treatment and required neck dissection as sal-vage therapy. In comparison, three patients out of the 19 who received the full dose prescription required neck dissection.

After following all 33 patients for a median of 32 months, the authors reported two-year survival and local and regional progression-free rates of 100%. One patient, who had per-

sistent hypoxia and was not de-esca-lated, developed lung metastases. The researchers will continue to follow the group and report disease control.

Side-effect incidence and toxic-ity were not reported separately for the de-escalated group. “Overall, the patients did very well,” said Lee. “Tox-icity was less, but given it was not a randomized trial, we don’t have any statistics to demonstrate the benefit.” The group plan to assess the impact of de-escalation on side effects in a separate study.

“This work is just touching the surface of this field,” said Humm. In a further follow-up study, the researchers plan to de-escalate both tumour and nodal dose from 70 to 30 Gy in patients selected using F-18 FMISO imaging. They aim to iden-tify how much dose can be de-esca-lated without compromising disease control. As in the current study, neck dissection has been selected as an effective salvage therapy for patients with disease that persists following treatment.

Jude Dineley is a freelance science writer and former medical physicist based in Bavaria, Germany.

PET conforms radiotherapy to tumour biology

The researchers: Nancy Lee and John Humm from MSKCC.

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A new way to evaluate DIR uncertainty Researchers in the US and Denmark have demonstrated a new way to evaluate the uncertainty of deform-able image registration (DIR), which tracks the changes of tumours in medical images. According to the study, which was based on real images of patients with prostate cancer, a “distance discordance met-ric” (DDM) is better able to evaluate uncertainties in DIR than existing methods. The new method should allow radiotherapists to provide can-cer patients with more accurate treat-ment plans (Phys. Med. Biol. 61 6172).

The aim of radiotherapy is to localize radiation to a tumour while sparing healthy tissue, so that a patient does not have to suffer more radiation than necessary. To do this, radiotherapists make use of medi-cal imaging, such as CT and MRI, to identify a tumour’s boundaries. But this is difficult if the relevant part of the body undergoes motion, or if the patient loses weight or if the tumour itself begins to change in size.

One way to monitor these changes is with DIR, a type of geometric transformation that maps individ-ual three-dimensional volumes or “voxels” of a patient’s anatomy from one image to the next. In principle,

DIR can help a radiotherapist track changes in a tumour site and thereby re-direct a course of radiotherapy.

But DIR is subject to its own uncer-tainties, particularly since there is no “ground truth”: a section of a liver, for example, can look just as vague on one image as on the next,

so there is no way to identify how its internal structure is changing. Vari-ous methods exist to evaluate these uncertainties, but they themselves have drawbacks – needing manual inputs, for instance.

DDM – introduced by medical physicist Joseph Deasy at the Memo-

rial Sloan Kettering Cancer Center and colleagues two years ago – is a new way to evaluate DIR uncertain-ties that begins by registering several images against one arbitrary refer-ence image. The software identifies voxels that happen to be in exactly the same location in the reference image, and then picks different reference images to see how far those voxels move. DDM measures uncertainty as a spatial distribution – that is, the average distance between voxels.

Testing the potential In a previous study, Deasy and col-leagues tested DDM on the DIR of a digital phantom for which they could pre-programme tumour growth and shrinkage. They found that the out-put of DDM was closer to the known error of DIR than the outputs of two other methods, inverse consistency error (ICE) and transitivity error (TE).

Now, however, the researchers have tested DDM on DIR-processed rectum and bladder images of real prostate cancer patients, treated at Haukeland University Hospital in Bergen, Norway. The results again showed that DDM was better than ICE and TE. “The spatial DDM uncer-tainty map clearly showed that the

regions of bowel gas resulted in poor registration, as well as the superior bladder due to bladder filling,” said Ziad Saleh, a member of Deasy’s group and lead author of the study.

Saleh noted that a visual inspec-tion of images by an expert “should remain the gold standard” before making any clinical decision on a radiotherapy programme. But he says that DDM has now been proven to be a good automated and quantita-tive tool to assess DIR uncertainties. “Upon further validation, DDM has the potential to be utilized in adap-tive planning to provide patient-specific treatments,” he added. “Furthermore, DDM can be used for robust optimization, especially in proton therapy, which is sensitive to uncertainties.”

The researchers are now investigat-ing how DDM can improve the qual-ity of the automated segmentation of images into different regions based on, for example, tissue type, using “atlases” of previous patient images. “Another area of interest is to under-stand the implication of the uncer-tainty on dose mapping,” said Saleh.

Jon Cartwright is a freelance journalist based in Bristol, UK

Colour wash representation: uncertainty maps using ICE, TE and DDM overlaid on a reference CT for an example patient. Deformed contours of the rectum and bladder from weekly CTs are also shown.

Radiation treatments delivered by real-time adaptive radiotherapy systems enable an increased dose to targeted tumours, administered with increased certainty over non-adaptive systems because they account for intrafraction motion. Several types of types of clinically implemented adaptive systems exist – multi-leaf collimator (MLC) track-ing using a conventional linac, a robotic tracking system, and a gim-balled tracking system – while couch tracking is in clinical development. Although geometric and dosimetric assessments have been performed for each, none previously had side-by-side comparisons.

A multi-institutional research team has conducted a dosimetric assessment of all types of real-time adaptive radiotherapy systems. They also tested the hypothesis that regardless of which system is used, dosimetric accuracy is improved compared to non-adaptive radio-therapy systems in the presence of tumour motion. The study find-ings confirmed their hypothesis that all adaptive systems accurately accounted for tumour motion and significantly outperformed non-adaptive delivery methods (Radio-ther. Oncol. 119 159).

A total of 10 cancer treatment centres participated in the study.

Systems evaluated included four MLC-based and two each of the robotic, gimballed and couch track-ing systems.

The researchers developed two treatment programmes – one for lung cancer and one for prostate cancer. Lung contours were obtained from a stage I non-small-cell lung-cancer patient. A tumour volume of 7.2 cm3 received 54 Gy in three fractions. Prostate contours were acquired from a patient with an average pros-tate volume of 55.3 cm3, receiving a stereotactic dose prescription of 36.25 Gy in five fractions. Common CT and structure sets were utilized. Each institution, however, had dif-ferent planning systems, dosimetry phantoms and motion platforms. All of the motion platforms had sub-millimetre accuracy.

Careful planningFour lung tumour and four prostate tumour motion traces were selected, to represent a variety of observed categories of motion for lung and prostate cancer. Each plan was deliv-ered twice to a moving dosimeter for each motion trace, with and without real-time adaptation. Each meas-urement was compared to a static measurement and the percentage of failed points for γ-tests recorded. Principal investigator Paul Keall, of the University of Sydney’s Radiation Physics Laboratory, and co-authors reported that all institutions pro-vided planning and dosimetric results for lung-cancer evaluations. Nine reported planning and dosi-metric prostate-cancer results.

The combination of data sets from all 10 institutions showed that there was a significant difference between real-time adaptive and non-adaptive radiotherapy delivery, for both lung and prostate treatments. All insti-tution measurement sets showed improved dose accuracy for lung traces, with a mean 2%/2 mm γ-fail rate of 1.6% with adaptation and 15.2% without it. The improve-ments in dose accuracy for prostate traces were comparable, with a mean 2%/2 mm γ-fail rate of 1.4% with adaptation and 17.3% without it.

The high-frequency motion traces resulted in the highest γ-fail rates for both lung and prostate cancers, while both the typical lung and the stable prostate traces resulted in the lowest γ-fail rates. Additionally, the accu-racies of the four types of real-time adaptation systems were comparable.

The authors wrote that “dosimet-ric failures were observed to be both inside the high-dose target volumes and in the low-dose areas toward the edges of the dose distributions, for both the lung and prostate cases. Lung results showed a greater num-ber of failures near the edge of the target volumes potentially because of the larger motion trajectories and steeper dose gradients.” While the delivery systems had key differences, such as motion detection, prediction and correction strategies, their per-formance results were similar.

The authors point out that unaccounted-for motion repre-sents the largest error in the treat-ment delivery chain. Keall told medicalphysicsweb that he believes this

well-documented fact may help hos-pital radiotherapy departments cost- justify the replacement of non-adap-tive radiotherapy systems with real-time adaptive ones. Another factor that will help justify this transition is the reduction in toxicity to patients, which will lower the costs of man-aging side-effects. And as technol-ogy matures, the cost of systems will decrease. Integrated imaging and delivery radiotherapy systems will also help patient throughput – enabling a department to increase its overall patient load and become more cost-effective.

Future systemsKeall observed that future adap-tive systems will be more sophisti-cated and will be able to conform radiotherapy delivery plans even more accurately and precisely to the dynamic anatomy and physiology.

“We know that tumours rotate and deform, and if multiple targets are being treated, that these targets can move independently of each other. Future adaptive systems will be able to improve imaging and tar-get delineation, improve treatment planning, and utilize data provided by improved clinical decision sup-port systems. As with the improved accuracy of today’s generation of real-time adaptive radiotherapy sys-tems, innovations in future systems will make the lives better for future cancer patients.”

Cynthia E Keen is a freelance journalist specializing in medicine and healthcare-related innovations.

Adaptation in real time ramps dose accuracy

Raman analysis: Andrew Jirasek uses an inVia Raman microscope to examine radiation damage.

Researchers at the University of Brit-ish Columbia (UBC) are using Raman spectroscopy to detect radiation damage in cells and tissues during radiotherapy. Currently, radiation dose is prescribed based on popula-tion averages and does not account for individual patient radiosensitiv-ity. The group is developing an early detection tool based on Raman spec-troscopy, performed either prior to the first treatment or within the first few fractions, with the ultimate aim of personalizing dose prescriptions. After conducting cell and animal model experiments, they are now at the point of testing the system on prostate cancer patients.

“This is a very powerful tech-nique,” UBC physicist Andrew Jirasek said. “Previously, the only outcome of treatment was disease status; for example, tumour size. Our hope is that Raman analysis will provide accurate treatment evalua-tion sooner.”

Raman reveals radiation harm

Reni

shaw

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MR-guidance: how great is the need?Online MRI-guided radiotherapy enables real-time, high-precision visualization of anatomical changes during treatment delivery. But with many image-guided radiotherapy (IGRT) options available already, how great is the need for large-scale in-room MR guidance? This was the question under debate at this year’s ESTRO 35 conference in Turin, Italy.

“Do we want a system that allows us to see what we are treating in real time? Yes absolutely,” said Frank Lohr, previously at University Medi-cal Center Mannheim, now at the Azienda Ospedaliero-Universitaria Modena. “But the economics have to be justified.” Lohr questioned whether online MRI guidance will really make a qualitative difference, or whether we should instead focus on exploiting the advanced image-guidance strategies that are already available. He indicated that online MRI guidance might have impli-cations in two areas: geometrical treatment accuracy and biologically/functionally driven strategies.

Lohr first considered the current accuracy status in radiotherapy. The main problem is breathing motion, which can create uncertainties in dose delivery and target coverage. Margins are applied to account for such motion, but at the expense of normal tissue irradiation; while approaches such as breath hold, gating and tracking enable margin reduction.

As for where the improved geo-metric accuracy may create a bet-ter outcome, Lohr says that it could benefit large lung and liver tumours, and possibly targets in the kid-ney and pancreas. For small lung and liver targets, it is unlikely that better geometric accuracy will fur-ther improve results. He also noted that current MRI-guided radiother-apy systems cannot deliver non-coplanar beams.

“We already have tools that get us to near perfect accuracy,” said Lohr, citing the Gamma Knife and CyberKnife radiosurgery systems, and motion tracking systems such as ExacTrac and Calypso. “And brachy-therapy already uses MRI guidance.”

So what level of accuracy can be achieved with guidance approaches available on conventional linacs today? Cone-beam CT (CBCT) with deep inspiration breath hold (DIBH) can achieve an accuracy of 2–3 mm, says Lohr, noting that DIBH used to be cumbersome and slow, but is now faster and easier to perform. This approach was facilitated by the development of flattening filter-free delivery and fast collimators that shorten the treatment dura-tion, as well as positioning devices such as surface scanners and fiducial tracking. In addition, recent work in applied physiology has indicated that breath holds of sev-eral minutes can be sustained with

minimal preparation.Another technology that may

return to mainstream use is ultra-sound, which offers excellent soft-tissue image quality where applicable and benefits from improved tracking algorithms.

Finally, Lohr considered MRI’s unique ability to image physiologi-cal variations. The ability to identify functionally active lung tissue and optimize radiation delivery to avoid these areas, for example, could prove of massive benefit. “But how much of this information is needed on a minute-by-minute basis?” he asked. “Could this be performed offline?” He noted that online MR-based func-tional imaging is limited by currently available field strengths. Should this change, however, and targets iden-tified that require high-resolution dose deposition and daily changes in targeting strategy, this could rep-resent the ultimate application of online MRI guidance.

Lohr reiterated the precision treat-ment delivery afforded by today’s IGRT approaches. “If we really need online MR guidance, shouldn’t we do everything we can with what we already have to get as near as possi-ble?” he concluded.

Making the case for MRI“The organizers gave me the easi-est job in the world…” declared the University of Sydney’s Paul Keall, “to convince you that the future of radi-otherapy involves integrated MR-guided machines.” Keall went on to list 10 reasons why the unparalleled soft-tissue contrast afforded by MRI is essential.

“It’s obvious,” he said. “We need to see the tumour anatomy throughout treatment.” He asked the audience to close their eyes and then shake hands with the person next to them. “This is what we’re doing now in radiotherapy.”

Keall emphasized that patient

motion is complex, with translations, rotations, deformations and changes in physical properties to account for. “Our patients are dynamic, our anat-omy is dynamic and our physiology is dynamic,” he said. And it’s not just target motion that needs tracking. If a tumour is located next to the heart, for example, MRI can visualize the beating heart to reduce treatment toxicity. And while ultrasound imag-ing may be cheaper, image quality is far superior with MRI and of particu-lar benefit in sites such as the kidney and liver.

Looking at the introduction of other advanced radiotherapy tech-nologies, a show-of-hands revealed that almost all of the audience now perform stereotactic body radiother-apy, whereas 10 years ago only about 20% were using this approach. Like-wise, almost everyone now employs some form of image guidance, while less than 10% were doing this 10 years previous. “I think that what we’re doing with MRI is the same,” said Keall.

He listed the many companies and institutions now building MR-guided radiotherapy devices. This includes ViewRay, with 20 confirmed sales to date and Elekta, which plans to ship 79 units by 2019 – a com-bined market of $1bn. Last year, the University of Alberta group founded Magnet-Tx to commercialize its Aurora RT, while both Siemens and the Australian MR-linac programme demonstrated prototypes.

Other reasons for implementing online MR guidance include the abil-ity to exploit existing MRI expertise, the lack of imaging dose and the ability to image actual anatomy as opposed to surrogates.

MR guidance could also enable radiation treatment of non-onco-logic diseases such as atrial fibril-lation, currently treated via an invasive, expensive procedure. By using MRI to image the beating heart

and define the small, moving target volumes, it’s possible to noninva-sively treat one of the most common conditions. And if physicians start to use radiation for this application, more radiotherapy departments will be needed.

Finally, Keall described the use of online MRI guidance to enable phys-iological targeting during radiother-apy, which no other technology can achieve. “Cancer physiology is het-erogeneous and changes with time,” he said, citing tumour hypoxia, which can change during a single treatment. “The ability to selectively image and target the most resistant parts of cancer could dramatically change cancer outcomes.”

Are we already good enough?Retaking the stage, Lohr addressed some of Keall’s arguments. Yes, MR guidance is obvious, he agreed, but only if you’ve got the money. With MR-guided systems costing three times that of other radiotherapy devices, the question is “how much good can we achieve with more imaging”. Lohr also noted that many professionals still do not concur that daily online imaging is useful.

Direct imaging of the tumour is already possible, said Lohr, if you treat in a static breath-hold situa-tion, which can be created today. He noted that using MRI to enable radiation treatments of atrial fibril-lation is indeed promising and mer-its evaluation.

As for functional imaging, Lohr again questioned whether currently available field strengths are suffi-cient and wondered which processes change within minutes and thus necessitate online imaging. Func-tional information could instead be gathered offline, he suggested, and integrated into treatment plans. “We shouldn’t feel too bad, because we’re already pretty good at what we’re doing,” he concluded.

Finally, Keall countered some of Lohr’s concerns. In terms of whether improved geometric accuracy leads to a better outcome, he emphasized that motion is the biggest error in the radiotherapy dosimetry chain. As for the inability of current MRI-guided radiotherapy systems to use non-coplanar beams, Keall explained that coplanar beams are most common in today’s treat-ments. “If it turns out that multiple coplanar beams are used more in the future, we can work to integrate MR machines to do this,” he said.

As for the system cost, Keall noted that when integrated PET/CT sys-tems were first introduced, people questioned the need to merge two expensive machines. But the benefit of integration was strong enough to justify itself, and all PET systems are now integrated with CT. “It is cost-effective to add image-guidance to reduce toxicity,” concluded Keall.

MR-guided radiotherapy: systems are being built by teams including (clockwise from top left) Elekta (with UMC Utrecht and others), the University of Alberta, the Australian MR-linac programme and ViewRay.

P A T E N T S

A round up of recent international patent applications.

Ultrasound guides radiotherapyAn ultrasonic imaging system for guiding radiotherapy is described by Philips (WO/2016/050709). The imaging probe includes a thin 2D array of piezoelectric transducers that can be attached using adhesive tape or a belt, minimizing the amount of pressure needed to maintain the probe in acoustic contact with the patient. The transducer array produces 3D images of the target region using electronic beam steering (with no moving parts), either during or between treatment fractions. The images can then be employed to adjust the treatment plan in response to any movement or displacement of the target anatomy.

Light guide offers real-time dosimetryDoseVue has developed a system for measuring the dose received by a patient during radiotherapy or interventional procedures (WO/2016/075180). The system comprises: a minimally invasive light guide that undergoes changes when exposed to ionizing radiation; a detector that quantifies the signal emitted by the light guide; and a control unit that calculates the dose received by the light guide. The light guide has a coating that acts as a place-dependent spectral filter and a second coating that includes luminescent material. When exposed to radiation, the luminescent component emits light, which is used to reconstruct the dose along the light guide.

Treatment system integrates imagingPanacea Medical Technologies has invented a radiotherapy apparatus integrated with a dual-kV source that performs stereotactic imaging and cone-beam CT with a large field-of-view (FOV). The apparatus comprises a ring gantry with a wide (over 700 mm) central opening, which includes at least two kV sources, at least two movable detectors in the ring gantry, and a linac X-ray tube. The first detector generates a full-fan mode imaging beam with a FOV of at least 250 × 250 mm, achieved by moving it close to the patient plane. The second detector can generate a half-fan mode beam with a FOV of 250 × 450 mm, by moving the detector towards the isocentre of the ring gantry (WO/2016/030772).

Dose-rate modulation spares OARsImpac Medical Systems has published details of a dose-rate-modulated stereotactic radiosurgery system (WO/2016/032798). The system receives medical images of a target and an organ-at-risk (OAR), as well as the target dose and OAR dose constraint. It then generates a dose application plan, based on these parameters. To generate the plan, the system determines the placement of an arc along which radiation is to be applied. It then divides the arc into a number of segments and determines a dose rate associated with each segment. Finally, the predicted OAR dose is calculated based on the determined dose rate and compared with the OAR dose constraint.

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8 symposium report

Medical physics: past, present and futureThis year, Physics in Medicine & Biology (PMB) celebrates its 60th anniver-sary. To mark the occasion, the jour-nal hosted a symposium at Imperial College London, as part of ICCR 2016. The 60th Anniversary Sympo-sium saw nearly 300 delegates from around the world join PMB board members and editors-in-chief, pre-sent and past, to find out more about the evolution of medical physics.

The symposium began with an opening address from PMB’s Editor-in-Chief Simon Cherry, from the Uni-versity of California, Davis. Cherry took a look back at the very first issue of PMB, and shared some of the jour-nal’s most cited papers and most pro-lific authors. The podium was then turned over to five of PMB’s current board members to examine the past, present and future of medical physics.

The medical-physics revolutionSteven Meikle from the University of Sydney described just how far medical physics has come in the last 60 years. Looking first at the current state-of-the-art in cancer diagnos-tics, he explained how this involves anatomical imaging with CT, ultra-sound or MRI, plus PET/CT scans for staging. Treatment planning can be based on CT, MRI or PET/CT, as can post-treatment imaging to monitor effectiveness. In 1956, only planar X-ray imaging was available. This was used for diagnosis, but not routinely for planning, while post-therapy monitoring relied solely on clinical observation.

For radiotherapy, treatment plan-ning in 2016 uses model-based or Monte Carlo methods. Radiation is delivered via conformal tech-niques such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), volumetric-modulated arc therapy (VMAT) and stereotactic body radiotherapy (SBRT), using X-rays, electrons, photons or ions. Verification is per-formed after, or even during, treat-ment delivery. In 1956, plans were hand-calculated based on anatomi-cal landmarks and delivered using kilovoltage X-rays or high-energy gamma rays.

“You can see by comparing work-flows that imaging has made a huge contribution to the way we practise cancer diagnosis and staging, and medical physics has played a big part in that,” explained Meikle. “Medical physics has also made a big contribution to the way external-beam radiotherapy is applied for cancer treatment.”

Meikle examined the major advances that enabled this “medical-physics revolution”. “In imaging, I nominate tomographic reconstruc-tion as the single biggest advance that moved the field forward,” he declared. Indeed, the significance of this development was recognized

back in 1979, when Allan Cormack and Godfrey Hounsfield won the Nobel Prize in Physiology or Medi-cine for their development of com-puter-assisted tomography.

In radiotherapy, major advances concern the emergence of conformal radiotherapy, including beam shap-ing with multi-leaf collimators in the 1980s, IMRT in the 1990s and IGRT in the 2000s. “All of these progress radiotherapy treatment planning and delivery to allow much more conformal and precise dose distribu-tions,” he said.

Meikle concluded by considering how such advances impact patients. “Over the last 60 years, medical physics has helped to reduce can-cer mortality and improve quality-of-life for cancer patients,” he said. “Life expectancy is greater now than 60 years ago. But we are also losing more years to ill health and disabil-ity. It’s easy to look back and think all the problems have been solved. But chronic illness is still a big prob-lem – and medical physicists are well equipped to help solve this problem.”

Evolutions in diagnostic imagingNext to speak, Brian Pogue from Dartmouth discussed the evolution of diagnostic imaging over the last 60 years. He noted that between the 1990s and 2000s, PMB saw a jump in imaging publications per year, with citations in this field growing even faster.

Pogue shared some example suc-cesses in medical imaging, such as low-dose CT, which was advanced by the development of new detectors, statistical modelling algorithms, iterative reconstruction and patient-

specific scans, as well as public aware-ness of the need for low-dose scans. PET/CT and SPECT/CT, meanwhile, evolved thanks to hardware develop-ments, improvements in reconstruc-tion and widespread adoption.

Another example is X-ray tomos-ynthesis for breast imaging, which was enabled by new detectors and sources, reconstruction algorithms, CAD algorithms and screening rec-ommendations. Elsewhere, dual- and multi-energy CT are now widely adopted, with the field in an expo-nential growth phase.

Then there’s 3D ultrasound, which has benefited from faster digitization and 3D reconstruction techniques. “This might look like a technical curiosity, but its impact has been profound in both neonatal and breast-cancer imaging,” Pogue pointed out. Other success stories include MRI breast and prostate applications, surgical guidance and radiotherapy positioning technolo-gies, near-infrared spectroscopy and robotic procedures.

Pogue also described the use of con-trast agents to improve resolution, contrast and function assessment, citing growth in the use of ultrasound microbubble contrast as one exam-ple. “We can use contrast agents to push imaging to its ultimate extent, by using super-resolution methods with bubble localization to achieve micron-level spatial resolution across a centimetre of tissue,” he added.

Finally, Pogue mentioned some fundamentally new physical-imag-ing techniques that use multiple electromagnetic or acoustic spectral bands to image tissue with com-bined information streams. These

included magnetic particle imaging, an embryonic field in a rapid growth phase, as well as photoacoustic imaging, bioluminescence and Cer-enkov imaging. “PMB has published some of the most important papers,” he noted.

See what you treatBas Raaymakers from UMC Utre-cht considered the need for image guidance during radiation therapy. With advanced modalities such as IMRT allowing the sculpting of dose distribution, it becomes imperative that radiation is accurately delivered to the correct place. “Image guid-ance becomes more and more criti-cal with these types of radiotherapy delivery,” he explained.

Changes in patient and tumour anatomy during a fractionated radiation course necessitate imag-ing between fractions to ensure the treatment remains accurate. “If you’re going to deliver radiation 30 times, things are going to change,” said Raaymakers. And even during treatment, motion due to breathing, for instance, can create uncertainties in dose delivery. Image guidance can help to mitigate such uncertainties.

Raaymakers described the wide range of options available for the guidance of external-beam radio-therapy. In-room CT-on-rails sys-tems offer imaging prior to, although not during, treatment. Megavoltage imaging with a treatment beam can be used before or during treatment and provides good bony-anatomy visualization, albeit with low con-trast and signal-to-noise ratio. Fluor-oscopy systems also offer real-time guidance during irradiation.

Ultrasound can now be employed for treatment guidance, with Elekta’s Clarity allowing inter- and intra-fraction imaging, and other systems offering inter-fraction ultrasound guidance. Other approaches include radiofrequency tracking of implanted beacons and on-board cone-beam CT. Further ahead, biological guid-ance may be possible, enabled by the PET-guided system under develop-ment by RefleXion Medical.

Ultimately, MRI may prove the optimal guidance modality, offer-ing real-time visualization of the tumour and its surroundings. As such, several groups worldwide are developing MRI-guided radio-therapy systems. The MRIdian from View Ray, for example, which is based on three cobalt-60 sources and a 0.35 T MRI, was first used to treat a patient at the start of 2014 and is now in regular clinical use.

The AuroraRT, developed at the University of Alberta, integrates a 6 MV linac with a 0.5 T magnet. The first prototype was operational in December 2008 and the system is now being commercialized by Magnet Tx. The Australian MR-linac project is also developing an integrated system, producing an operational prototype in January of this year.

Raaymakers and colleagues at UMC Utrecht, Elekta and Philips have developed a high-field MRI-guided radiotherapy system that integrates a 1.5 T MRI with a 6 MV linac. The first prototype was built in 2009, and a clinical system is now under construction and being com-mercialized by Elekta under the name Atlantic.

“Image guidance is a major research arena for radiotherapy, and MRI guidance offers great poten-tial,” Raaymakers concluded. “Sight during treatment enables better targeting, better sparing and better dose-response assessment.”

New horizons in adaptive therapyOnce it is possible to “see what you treat”, the next step is to perform adaptive radiotherapy (ART). Katia Parodi from Ludwig-Maximilians-Universität München examined the key ingredients of modern ART, explaining first how the use of graphics processing units (GPUs) to accelerate computation made a huge impact in this field.

GPUs can run accurate Monte Carlo-based VMAT dose calcula-tions in less than 40 s – opening up the possibility of dose recalculation while the patient is on the table. “This could allow us to go towards plan-of-the-day adaptation,” noted Parodi. Accelerated dose calculation also applies in particle therapy, where GPU-based Monte Carlo proton cal-culations have been achieved in less than 4 s per million particles.

Rapid computation also enables

The symposium speakers: Editor-in-Chief Simon Cherry (top) opened the event by presenting the first issue of Physics in Medicine & Biology. Brian Pogue, Bas Raaymakers and Katia Parodi (bottom row, left to right) discuss the state-of-the-art in medical imaging, image-guided treatments and adaptive radiotherapy.

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symposium report 9

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One of the primary weaknesses of the traditional point-based MU verification approach is that there can be one or multiple significant dose discrepancies elsewhere in the field(s), beyond the regions that directly impact the chosen point(s). In IMRT and VMAT, complex intensity distributions exist within each field and contribute to optimized dose distributions in the full patient geometry that cannot be adequately verified by simple numerical The next and necessary evolution of the secondary dose calculation process will require verification of all patient dose distribution points (i.e., the full patient dose volume) to adequately account for the myriad variations inside the treatment fields as generated for IMRT, VMAT, and other complex modern treatment techniques. The method utilized to perform this verification involves a secondary calculation of the full patient dose volume using a robust, modern dose calculation engine (e.g., Superposition/Convolution). The input for this process is the field intensities as a function of time, most often captured by the DICOM RT

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the application of advanced planning strategies, such as multi-criteria opti-mization (MCO), in which multiple plans are calculated and optimized. MCO is already deployed for photons and under development for ions.

Another critical ingredient is in vivo dose reconstruction. “If you can reconstruct the actual delivered dose, this could open a new way to docu-ment treatment,” said Parodi. “And if you can do this fast enough, it may even be possible to correct the treat-ment if something is going wrong.”

Parodi described some novel methods for in vivo dose reconstruc-tion in photon therapy, including Cerenkov imaging and thermoa-coustics. For particle therapy, she highlighted the recent renewed interest in ion-based transmission imaging for planning. Likewise, approaches such as PET, prompt gamma imaging and ionoacoustics are under investigation for monitor-ing dose delivered during treatment.

Looking forward, Parodi suggests that we may now be entering the era of biological guidance. “The next dimen-sion to explore for ART is biological guidance,” she told the delegates. One example is the use of PET for stratifi -cation, therapy personalization and response assessment. Including the oxygen-enhancement ratio in ion-

beam planning, meanwhile, could enable dose-or-cell-killing painting of inhomogeneous tumours.

Parodi concluded by presenting some emerging methods that exploit biology. These include micro- and minibeam therapies, spatially frac-tionated approaches designed to spare healthy tissue that have been demonstrated with both photon and proton beams. Another possibility is to use nanoparticles for tumour vas-cular disruption during radiotherapy.

The next 60 yearsThe fi nal speaker, Robert Jeraj from the University of Wisconsin, faced the hardest task – predicting the future. For a physicist, this usually

involves examining current trends and extrapolating. But the future is not always clear: “Even 10 years ago, people did not predict some discov-eries like immunotherapy,” he noted.

Jeraj suggested that medical phys-ics is one in spirit with medicine, and may progress along a similar path. He cited the “four P’s of medicine”: prediction of an individual’s disease development; personalized treat-ment; pre-empting disease before it occurs; and the participation of patients, communities and health-care providers. This rationale gives rise to the idea of precision medicine, which addresses the highly heteroge-neous nature of cancer. In the past, little could be done to tackle this, but

the emergence of targeted therapies is bringing personalized therapies within reach.

Unfortunately, there are obstacles to overcome. For example, cancers evolve in time to become harder targets to treat. So how can medical physics help? “We need to capture the whole disease and the evolution of disease, using multi-modality imaging techniques such as optical and molecular imaging,” explained Jeraj. In radiation therapy, such a shift from anatomical imaging and population-based treatment to molecular imaging, patient-specifi c therapies and non-uniform dose delivery is the foundation of “bio-logically conformal radiotherapy”.

Jeraj noted that medical phys-ics must also strive to treat more advanced cancers. He described a case in which the PET imaging of a patient with advanced meta-static prostate cancer revealed multiple, extremely heterogene-ous, lesion responses: responding, non-responding, stable, emerging and disappearing. “How can you treat this patient with one modal-ity? You can’t,” he said. But such information would possibly enable selective localized targeting (by radiotherapy, for example) of selec-tive non-drug-responsive lesions.

“Radiotherapy can be exploited to the large advantage of patients with highly advanced disease.”

This idea of extracting large amounts of useful data from a single medical scan is the premise underly-ing radiomics – a promising emerg-ing fi eld. However, much more data are available from genomic and other tests. To analyse such large amounts of data, says Jeraj, we must learn from “big-science” physics approaches. When analysing data to detect the Higgs boson, for exam-ple, CERN physicists relied on a deep understanding of the underlying fundamental physics.

“Likewise, when we move to medicine, we have to understand the underlying biological principles that drive observations,” Jeraj explained. Image analysis and modelling of disease require accurate knowl-edge of the biology. To achieve this effectively, it’s essential that physi-cists partner with biologists. “These problems are way too hard to tackle alone,” he said.

With medical physics perhaps on an inevitable path towards incorpo-rating more and more biology, what could the next 60 years hold for PMB? According to Jeraj, by then, the journal may require a name change – to Physics & Biology in Medicine.

Yesterday and tomorrow: Steven Meikle (left) examines the evolution of medical physics since 1956, while Robert Jeraj aims to predict the future.

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particle therapy 11

Switzerland’s Paul Scherrer Institute (PSI) developed the technique of pencil-beam scanning (PBS) proton therapy 20 years ago and continues to be a pioneering global leader in its use. In newly published studies, researchers at PSI’s Center for Proton Therapy report that this technology has produced excellent outcomes in children with rhabdomyosarcomas (RMS), and is effective and safe for the treatment of patients with skull-base tumours.

RMS, a cancer that normally develops in skeletal muscles, is the most common soft-tissue sarcoma in children. Paediatric patients with RMS are typically treated with sur-gery, chemotherapy and/or radio-therapy. Damien Weber, head and chairman of the Center for Proton Therapy, and co-authors conducted a study of all children with RMS who received PBS proton therapy at PSI (Radiother. Oncol. doi: 10.1016/j.radonc.2016.05.013; Pediatric Blood & Cancer doi: 10.1002/pbc.25864).

The study included 83 of 91 chil-dren treated between January 2000 and December 2014, 51.8% of whom had parameningeal RMS (PR-RMS, which represents approximately 15% of all RMS in children). In addi-tion to proton therapy, all patients also received chemotherapy. Treat-ment plans were optimized to maxi-mize gross tumour volume (GTV) coverage and not exceed organ-at-risk (OAR) dose constraints. A com-bination of single-fi eld uniform dose (SFUD), intensity-modulated proton therapy (IMPT) and SFUD+IMPT plans were used. Patients received a median dose of 54 Gy(RBE), admin-istered in a median of 30 fractions over 30 to 59 days.

Patients with PM-RMS initially underwent 3D planning with co-registered CT and MRI, and had sub-sequent CT scans throughout their treatment. These patients had posi-tioning checked before the delivery of every 1.8–2 Gy(RBE) fraction to the primary tumour and involved lymph nodes. The median planning target, a 1 cm extension of the GVT, received a dose of 50.4–55.8 Gy(RBE). Dose constraints to OARs were deter-mined as maximum of 54 Gy(RBE) to the brainstem, 50.4 Gy(RBE) to the spinal cord, 54 Gy(RBE) to the optic chiasm and optic nerves, and mean dose to at least one cochlea of 36 Gy(RBE).

Twelve patients developed grade 3 acute toxicities, none of which required radiotherapy interruption. There were 16 events of grade 3 late toxicities in 15 patients. Twelve of these patients, nine of whom had orbital RMS, developed radiation-induced cataracts that required subsequent surgery. One patient developed a unilateral hearing impairment. All patients who devel-oped grade 3 late toxicities also expe-rienced tumour recurrence.

Local failure occurred in 16 patients

(19.3%) during a median follow-up period of 55.5 months. The majority of these had local recurrence within one year of radiotherapy. Tumour location and size, and group/stage were signifi cant predictors for local failure. Fourteen patients died from tumour progression, nine of whom had PR-RMS. The fi ve-year local con-trol and overall survival rates were 78.5% and 80.6% respectively.

A quality-of-life survey deter-mined that the children were quite resilient. Baseline surveys were low, but improved two months after completion of radiotherapy. After two years, patients were compara-ble with a healthy control group. The team concluded that PBS proton therapy led to excellent outcomes in children with RMS, with minimal late non-ocular toxicity and good quality of life.

Skull-base treatmentsAt PSI, PBS proton therapy is also used to treat skull-base tumours, including chordoma and chondro-sarcoma (ChSa). Chordoma is a rare tumour characterized by local aggressive growth and local recur-rence; ChSa is a rarer bone tumour. A study of 151 chordoma patients and 71 patients with low-grade ChSa treated between October 1998 and October 2012 evaluated long-term tumour control and toxici-ties (Radiother. Oncol. doi: 10.1016/j.radonc.2016.05.011).

All patients underwent surgery before proton therapy. Their mean GTV following surgical resection was 35.7 cm3, and nearly one third of patients had a postoperative tumour abutting the brainstem or optic apparatus. Prescribed doses were 74 Gy(RBE ) for chordoma and 70 Gy(RBE) for ChSa, with an administered mean fraction of 1.8–2.0 Gy(RBE).

Patients were followed for up to almost 15 years. During this time, 29 patients died from their disease, nine of whom from local progres-sion. Local failures were experienced by 15.7% (30 chordoma and fi ve ChSa patients), half of which occurred within two and three years, respec-tively, following treatment. The estimated fi ve- and seven-year local control rates for chordoma patients were 75.8% and 70.9%, respectively. ChSa patients had a local control rate

of 93.6% for both time frames.The only distant failures that

occurred were in eight chordoma patients who also had local tumour recurrence. Metastasis-free survival for chordoma patients at seven years was 91.6%. The majority of patients (87.2%) did not experience any high-grade late toxicities within the fi rst seven years following proton ther-apy treatment.

Weber and colleagues reported that compression of the optic appa-ratus of the brainstem, histology and a GTV greater than 25 cm3 were signifi cant independent prognostic factors for both local tumour control and overall survival. Concluding that PBS proton therapy is an effective treatment for skull-base tumours, the authors recommended that such patients should have brain MRI scans twice yearly during the first three years following treatment, annually for the next four years, and every two to three years thereafter.

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Pencil-beam pioneers: Damien Weber and the research team at PSI.

In vivo feedback: the Prompt Gamma Camera (behind the phantom) detects the prompt gamma rays emitted during proton treatment.

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Prompt gammas verify the range The clinical team at Penn Medicine has successfully deployed IBA’s Prompt Gamma Camera during a patient treatment using pencil beam scanning (PBS) proton therapy. Since June 30 of this year, the Prompt Gamma Camera has been operated by the Penn Medicine team at the Roberts Proton Therapy Center in Philadelphia in several fractions of proton therapy delivered to treat a patient with a brain tumour.

This world-fi rst clinical applica-tion in PBS mode showcases the unique capacity of this new technol-ogy – specifi cally that it provides in vivo feedback on the proton beam penetration depth within the patient on an individual spot basis; thus allowing unprecedented quality con-trol of the target volume coverage.

“This is the second IBA Prompt Gamma Camera prototype that has been successfully deployed in clinics,” said IBA’s research director

Damien Prieels. “We are extremely excited by this achievement, which rewards the efforts of our dynamic network of academic, industrial and clinical partners to overcome the technical challenges that arose from this unique treatment modality. We are delighted and honoured to bene-fi t from the University of Pennsylva-nia’s expertise in pioneering the use of our new technology, which has just added to the clinical advantages of proton therapy.”

“This highly technical and chal-lenging project brought together rep-resentatives from the academic and clinical world to form a truly excep-tional team,” added James Metz, chair of radiation oncology at the Perelman School of Medicine at the University of Pennsylvania and executive direc-tor at OncoLink. “This is a very excit-ing time for us, as the results of this work may have an impact for the entire proton therapy community.”

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12 particle therapy

Hybrid scheme eases clinical bottleneckA US proton therapy centre with an oversubscribed scanning beam gan-try is reducing patient waiting times with a hybrid of intensity-modulated proton therapy (IMPT) and passive-scattered proton therapy (PSPT).

IMPT delivered by a scanned beam is increasingly popular. It delivers dose distributions that are significantly more conformal than those produced by passively scat-tered protons and spares healthy tissue more effectively than pho-tons. However, in 2014, staff at the University of Texas MD Anderson Cancer Center found that the clin-ic’s single scanned beam gantry was oversubscribed.

“Since IMPT can only be delivered by the scanning beam gantry, it is used from 4 am to midnight – but the other three scattering gantries finish treatments pretty much in normal working hours,” explained Shengpeng Jiang, a physicist at Tianjin Medical University Cancer Institute and Hospital in China and at the time, a visiting scientist at MD Anderson. “Some patients can-not be scheduled on the scanning beam gantry.”

Jiang and colleagues investigated the potential of an IMPT and PSPT hybrid, dubbed HimpsPT, as an alter-

native to IMPT that could solve the scheduling problem. They started by retrospectively generating HimpsPT plans for three patients already treated with IMPT (Int. J. Particle Ther. doi: 10.14338/IJPT-15-00014.1).

Replanned casesThe first case was a squamous cell carcinoma at the base of the tongue, with the dose prescribed to a pri-mary target and two nodal volumes. The second case was an individual with residual disease after resection of a skull base chordoma. The third was an individual with stage IIIB non-small cell lung cancer in the left lower lobe.

The team deliberately chose diffi-cult to treat tumour and organ-at-risk

(OAR) geometries. “By replanning these cases using HimpsPT, we were assured that it can be applied to almost every IMPT case,” said senior author Xiaodong Zhang.

IMPT beam arrangements were typical of those used clinically at the centre. With PSPT, dosimetrists aimed to spare normal tissue to the same extent as with IMPT. They did, however, allow greater tumour het-erogeneity and reduced conformal-ity in the PSPT plan, anticipating improvement upon combining with the IMPT plan. IMPT and PSPT plans were combined with equal weight-ing for delivery on alternate days.

In general, HimpsPT tended to provide a compromise between the respective benefits of IMPT and

PSPT. PSPT apertures at MD Ander-son produce a narrower penumbra than the scanning beam, with the potential to better spare normal tis-sue. However, IMPT using a scanning beam is inherently better at deliver-ing a homogenous dose that con-forms to the tumour volume.

In the chordoma plan, for exam-ple, HimpsPT spared the brain stem better than IMPT. Its maximum dose was 51.5 Gy versus 56.4 Gy with IMPT (radiobiological equivalent, RBE). Gross tumour volume (GTV) coverage was comparable, with a D99 (dose received by 99% of the vol-ume) of 66.0 Gy for HimpsPT versus 66.5 Gy for IMPT. Both HimpsPT and IMPT provided more homogene-ous and conformal coverage of the

tumour than PSPT.The authors assessed the robust-

ness of HimpsPT plans by incor-porating setup and proton range uncertainties into the plans and repe at i ng dose c a lcu lat ions . HimpsPT gave more robust target coverage and comparable OAR coverage to IMPT in head-and-neck and lung cases. For the chordoma, IMPT was actually more robust than PSPT due to a small GTV of 4 cm3. However, the authors argued that HimpsPT was still preferable for its superior OAR sparing.

Based on their findings, the authors began to prospectively prepare HimpsPT plans for patients initially planned using IMPT. Since then, 100 patients have been swapped to HimpsPT. “Currently, all patients can be scheduled on time because of this technique,” said Zhang.

“We are sure this technology will benefit other centres with similar workloads,” said Jiang, adding that clinics adopting HimpsPT should schedule extra time to allow prepa-ration and careful comparison of HimpsPT and IMPT plans. Effective communication between all staff groups in radiation oncology, and with the patient, is also essential, Jiang told medicalphysicsweb.

Scientists in Switzerland have found that boron carbide transmits nearly one-third more protons in the right direction than graphite when used as a degrader for proton therapy. The result suggests that boron carbide could reduce treatment times, with particular benefits for those under-going eye treatments (Phys. Med. Biol. 61 N337).

Proton therapy is similar to con-ventional radiotherapy in that it is used to destroy tumours, but in prin-ciple has a finite range that spares surrounding healthy tissue. A cyclo-tron can be used to generate the pro-tons, but these protons will always have the same initial energy and, if left unchecked, can pass through the body, having little effect at all. For that reason the beamline’s operators must insert a degrader in the path of the protons; in general, the thicker the degrader, the less the protons’ penetration depth in the body.

Good degrader materials are those that are able to curb the energy of the protons without scattering them too much. In practice, this means a material with a high density and a low atomic number. Graphite (the allotrope of carbon, which has an atomic number of 6) is a com-monly used degrader, but Marco Schippers and colleagues at the Paul

Scherrer Institute (PSI) in Villigen thought they could improve on it with boron carbide, which is slightly denser yet (containing boron, of atomic number 5) has on average a lower atomic number.

As there are well-known physi-cal formulae to estimate energy loss and scattering, Schippers and col-leagues were able to work out the fraction of protons that is not scat-tered out of the bounds of the PSI beam transport system by either graphite or boron carbide. Their calculations showed that the trans-

mission for boron ought to be 37% greater than graphite.

Experimental proofThe PSI group followed up their cal-culations with experiments at the PSI PROSCAN facility, using real degrad-ers made of graphite and boron car-bide, adjusted such that both gave the same amount of energy decrease. They tuned their cyclotron so that it delivered the same number of pro-tons per second, and recorded the number of the particles that, having passed the degrader, still fell within

the bounds of metal collimators. The experiment showed that the

transmission for boron carbide was indeed greater than graphite, by 30% – almost the same as predicted by the simulations. “The boron-car-bide degrader scatters the beam less than the normally used degrader mater ial, graphite,” explained Schippers. “Therefore, more pro-tons will leave the degrader in the correct direction.”

This greater transmission could be good news for those having to undergo proton therapy on the eye. During such treatments, the protons should not pass through the eye’s lens, therefore patients are usually asked to focus on a bright spot away from the proton beam – a tiring demand, particularly if irradi-ation times are long. With a greater proton transmission, a boron car-bide degrader could reduce irra-diation times compared with those given by graphite.

First, however, Schippers and colleagues must build a clinically usable boron carbide degrader. “We need to do more extensive and accu-rate tests and measurements of the actual energy loss,” said Schippers. “If successful, we intend to install it permanently in our beam line at PSI.” He adds that they will also need to modify their computer con-trol systems, which place exactly the right thickness of boron carbide into the path of the beam. “Of course, the effects of all changes have to be veri-fied in clinical conditions before a real treatment is performed.”

Clinical case: a patient is swapped from IMPT to HimpsPT for a lung tumour retreatment. IMPT has the most conformal dose, PSPT the best spinal cord sparing and tumour coverage, HimpsPT provides a compromise.

Boron carbide best for proton degradation

The degraders: half of a graphite degrader installed at PROSCAN (top left); graphite wedges in the beam trajectory (top right); boron carbide block used in this work (bottom), the arrow shows the beam direction.

Miami Cancer Institute has chosen RayStation as the treatment plan-ning system for its new proton ther-apy facility, which will be the first in South Florida. The facility will serve a wider region, giving patients in Latin America and the Caribbean access to the benefits of proton therapy.

RayStation will be used for all pro-ton treatment planning at Miami Cancer Institute and the installation will include advanced features such as deformable registration, dose accumulation and adaptive radia-tion therapy. The facility will also be one of the early adopters of Ray-Station’s Plan Explorer tool, which enables automatic generation of a large number of plans for defined clinical goals and combinations of treatment techniques and machines.

“The proton therapy facility is truly starting to take form, with the cyclotron now in place and our treat-ment planning system selected,” said Minesh Mehta, deputy director and chief of radiation oncology at Miami Cancer Institute. “We are pleased to partner with RaySearch, which has a very successful track record in providing advanced technologies to cutting-edge centres such as ours. We anticipate a long relationship that will include the implementation of new technologies in the years to come.”

Florida proton centre selects RayStation

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Biological optimization for helium ionsHelium ion beams offer potential advantages for use in radiation ther-apy, including lower lateral scatter-ing than proton beams and a reduced fragmentation tail compared to heavier ions. But before helium ions are applied clinically, it’s essential to perform treatment planning studies to ascertain their biological effect in clinically-relevant scenarios.

The Heidelberg Ion Beam Therapy Center (HIT) in Germany plans to begin treating patients with He ions before the end of 2017, while CNAO, the National Centre of Oncological Hadrontherapy in Italy, is investi-gating the approach as a possibility for the future. With this in mind, a research team headed up at CNAO and HIT developed a model for quantifying the relative biological effectiveness (RBE) of helium ions (Phys. Med. Biol. 61 888). In their most recent work, the researchers refined this RBE model to predict the biologi-cal effect of 4He ion beams in a clinical scenario (Phys. Med. Biol. 61 4283).

Mixed radiation fieldDuring an actual treatment, inter-actions between the primary beam and the patient’s tissues will result in a mixed radiation field. “This field is composed mainly of primary and secondary He ions (4He and 3He) and secondary protons, deuterons and tritons,” explained first author Andrea Mairani. “Hence, we also have to biologically weight H sec-ondaries. For that, in this version of

the approach, we have used a phe-nomenological model introduced by Wedenberg et al [Acta Oncologica 52 580]”.

The team’s original model was based on published in vitro experi-mental values and developed within the framework of the linear-quad-ratic (LQ) model, as a function of the helium linear energy transfer (LET) and the tissue-specific radiosensi-tivity parameter (α/β) of photons. For this latest work, they refined the model by restricting it to a sub-set of the most relevant experimental data.

To calculate a biologically opti-mized 4He plan, Mairani and col-leagues integrated their biological model in the Monte Carlo Treatment Planning (MCTP) tool, which is based on the FLUKA Monte Carlo code and uses scanned pencil beams, as avail-able at HIT and CNAO. The plan was optimized by applying a quadratic exponential (QE)-based parameteri-zation (fQE) for the αHe term and the LET-dependent formalism for βHe.

The researchers simulated cell survival and RBE for a biologically optimized spread-out Bragg peak

(SOBP) in water, representative of a clinically-relevant scenario, for human adenocarcinoma cells. They then compared the simulations with cell survival experiments using the 4He plan, performed at HIT.

Comparisons of the predicted cell survival and RBE values with meas-urements showed that the model overestimated cell survival, with improved agreement in the distal part of the SOBP, where the dose-averaged LET (LETD) increases. The measured average RBE in the entrance channel was 1.17 ± 0.04, higher than the average calculated value of 1.03. In the target region, the calculated RBE increased, in line with the measured data.

Sensitivity studyMairani and colleagues also per-formed forward re-calculations of the optimized plan to investigate the variation of predicted cell survival when using three different param-eterizations – fQE; a linear quadratic function (fLQ); and a linear Gauss-ian-like function (fLE2) – for the αHe term. The fLQ and fLE2 functions gave similar cell survival results, ranging from about 7% (plateau region) to 20% (target region) lower than the fQE data. In the high LETD region, the three parameterizations gave similar estimations.

The researchers also compared the experimental data against predic-tions by more complex biophysical models: the local effect model (LEM)

and the repair-misrepair-fixation (RMF) model. LEM data agreed with model-predicted data to within 6% in the entrance and SOBP regions, while differences of about –23% were seen in the distal fall-off region. On average, LEM predicted a 13% higher RBE in the fragmentation tail.

The RMF model predicted lower RBE values at all depths, from 3% at the entrance to 31% in the RBE peak. In the fragmentation tail, RBE val-ues were around 18% lower. In gen-eral, RMF model-based calculations matched the experimental survival data well.

For the approach developed in this work, the mean absolute sur-vival variation between predic-tions and experimental data was 5.3 ± 0.9% . For the LEM and RMF models, the values were 4.5 ± 0.8% and 5.8 ± 1.1%, respectively.

Given the satisfactory results found for calculating RBE for a SOBP, the introduced formalism will be used to support future 4He ion-based treatment planning at HIT and CNAO. The researchers are currently refining the model used to describe the biological effect of H secondaries. “Additionally, we have started performing treatment plan-ning studies in water, applying the HIT clinical settings and using the developed Monte Carlo treatment planning tool,” explained Mairani. “This gives us the uppermost accu-rate description of the mixed radia-tion field.”

HIT researchers: (left to right) Andrea Mairani, Thomas Tessonnier and Ivana Dokic. Tessonnier holds a film irradiated with 4He ion beams.

The field of stray neutron radiation generated in gantry rooms as a by-product of scanning proton therapy has been mapped out by a team of European researchers. The results of their study may help to refine proton therapy treatments and help inform secondary cancer risk (Phys. Med. Biol. 61 4127).

Compared with other external-beam radiation treatments, proton therapy’s advantages lie in its more precise dose distribution and mini-mal exit dosing. Despite these advan-tages, however, proton therapy is not without its complications. Proton beams can unintentionally generate stray neutrons within the beam line elements, the structure of the gantry room and even within the patients themselves. These neutrons increase the risk of secondary cancer.

“Although the stray neutron dose is much lower in magnitude com-pared to the therapeutic proton dose, it penetrates the whole body of the patient and is not negligible,” explains Vladimir Mares, a physi-cist from the Helmholtz Zentrum München. This issue is of particular concern for paediatric patients, who

are more susceptible to the risk of radiation-induced cancers, and have an increased risk of developing sec-ondary cancers later in life.

Neutron measurementsTo evaluate the effects of these sec-ondary radiation doses, it is first necessary to determine the ener-gies and distributions of the stray neutrons generated by proton therapy. To achieve this, measure-ments are made with Bonner sphere spectrometers, which are capable of recording the neutron spectrum at a given point. While many studies have analysed the higher-risk neu-tron environment created by pas-sive scattering proton therapy – the more common delivery technique, in which the proton beam is spread by a scattering medium – few have looked at the neutron spectra gen-erated by scanning proton therapy, in which magnets are used to direct the beam.

In their new study, Mares and his colleagues measured the stray neu-tron environment around an anthro-pomorphic, paediatric phantom using two different Bonner sphere spectrometry systems, and analys-ing the data using a variety of unfold-ing codes. Each time, the phantom was irradiated with a pencil proton beam with energies of 100–144 MeV

– simulating the treatment of a 5 cm-diameter target tumour located in the centre of the phantom’s brain.

In successive tests, the spheres were placed at a variety of positions around the phantom, recording the neutron spectra at different distances (up to 3.25 m away) and angles from the beam line. One sphere was also placed close to the floor, to investi-gate the potential effect of additional neutron scattering from the floor.

The team found that the ambi-ent dose equivalent decreased with

increasing distance from the phan-tom and angular position with respect to the beam axis. The neu-tron spectra showed similar ther-mal energy components all around the phantom, but higher energy neutrons (those above 20 MeV), however, were only detected at positions close to the beam axis. Off-f loor scattering was seen to be insignificant.

“These results could be of direct clinical relevance and could lead to practical changes in dose prescrip-

tion,” said Mares. “They would also be of great use for shielding design, radiation zoning and other radiation safety studies.”

Both spectrometry systems were seen to provide similar measures of the neutron spectra, with differ-ent unfolding codes having limited effect. The team also compared their results to those from a previ-ous study, in which they had used a water, rather than an anthropomor-phic, phantom, and found a gener-ally good agreement between the two studies.

The study “provides the most com-prehensive information available on measured secondary neutron spec-tra from proton therapy,” comments Rebecca Howell – a radiation physi-cist from the University of Texas who was not involved in this study. Highlighting the use of the different spectrometer systems and unfold-ing codes, she adds, “the similarity of results regardless of methodol-ogy demonstrates the validity and robustness of the results.”

With this study complete, the researchers are now concentrating on developing proton therapy simu-lations with refined beam character-istics, treatment room models and uncertainties arising from the use of different codes and intra-nuclear cascade models.

Spectrometry system: experimental setup showing the Bonner spheres, within the gantry room at the Bronowice Cyclotron Center in Kraków.

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Researchers in the Netherlands have stepped closer to an ultrahigh-per-formance time-of-fl ight (TOF) PET system, demonstrating a new detec-tor that outperforms commercial state-of-the-art devices across sev-eral parameters. Comprising a mon-olithic crystal scintillator with two photosensors coupled to its front and back, the detector could help enable several emerging PET applica-tions (Phys. Med. Biol. 61 4929).

“We are highly excited and can’t wait to build a system to demonstrate the clinical value of this detector,” said senior author Dennis Schaart, leader of the TOF PET group at Delft University of Technology. “It will allow PET imaging at lower doses, with shorter scan times, with much better resolution and sensitivity.”

The researchers are targeting the detector for use in hybrid TOF PET/MRI and TOF PET/CT systems. Here, superior TOF, resulting from lower coincidence resolving times, can improve the detection of small lesions in whole-body scans. At the same time, higher spatial resolution enables more accurate imaging of specifi c organs, such as the brain.

Consequently, paediatric, neu-rology and breast imaging, and the detection of small metastases in can-

cer patients could all benefi t from the new detector. They could also enable more accurate quantitative molecu-lar imaging studies. “[This] is cru-cial to the development and clinical implementation of personalized medicine approaches in many types of disease,” said Schaart.

Dual-sided constructionThe detector uses two digital silicon photomultiplier (dSiPM) arrays opti-cally coupled to the front and back of the monolithic LYSO:Ce crystal in a dual-sided readout (DSR) confi gura-tion. Twenty-two millimetres thick, the commercially available scintil-

lator is a single, continuous block of crystal with a cross-sectional area of 32 × 32 mm. Each photosensor comprises a 32.4 mm square array of 64 dSiPM pixels. Each pixel com-prises 3200 microcells that, in turn, each contain a single photon ava-lanche photodiode and individual control and readout electronics.

The Delft PET group already dem-onstrated the superior performance of a 10 mm thick monolithic crystal read out by a single dSiPM array over the conventionally used combina-tion of narrow crystals and large, analogue photomultipliers. Then, the dSiPM array was positioned at

the back of the crystal, in a back-sided readout (BSR) confi guration. In using two photosensors, the new DSR design counteracts deteriorations in spatial, temporal and depth-of-inter-action (DOI) resolutions that occur with increasing crystal thickness. Meanwhile, the 22 mm-thick crystal detects photons with significantly greater effi ciency than the sub-10 mm crystals that have demonstrated the highest resolutions to date.

The researchers characterized the DSR detector with a series of irradia-tions using a collimated 22Na source, comparing it against a BSR detec-tor with the same crystal thickness. They measured a spatial resolution of 1.1 mm, quantified by the full-width at half-maximum (FWHM), compared to 1.7 mm for the BSR detector and around 4 mm in state-of-the-art PET systems. Temporally, the experiments revealed a coinci-dence resolving time of 147 ps, ver-sus 214 ps for the BSR detector and 325–400 ps in commercial high-end scanners. The DOI resolution was 2.4 mm (FWHM) versus 3.7 mm for the BSR version. There are currently no commercial whole-body scan-ners with DOI capability.

Schaart predicts “outstanding” performance in a clinical system

using either DSR or BSR detectors. The DSR detector, however, is more expensive and quantifi cation of its benefi ts in specifi c clinical scenarios such as the detection of small lesions is important, he said. The group is investigating this in collaboration with researchers at the University of Pennsylvania.

Currently, the researchers have no timeline for when the fi rst PET sys-tem with a complete ring of the new detectors will be constructed. “I’m convinced we will succeed in this, but in today’s funding climate it is hard to predict how much time it will take,” said Schaart.• In an accompanying paper, Schaart and colleagues demonstrated prac-tical techniques that calibrate the detectors and estimate the position and time of photon interactions. To date, complex and time-consuming algorithms have limited the use of monolithic crystals. The new algo-rithms are modifi ed versions of tech-niques previously developed by the group. Applied to the simpler BSR detectors they cut calibration times from around eight days to nine hours and sped up position and time esti-mations by a factor of 200. The same techniques were applied in the DSR study (Phys. Med. Biol. 61 4904).

Double take: the dual-sided detector (left) optically couples dSiPMs to the front and back of a LYSO:Ce crystal. This is a modifi ed version of a previous detector with a single dSiPM coupled to the crystal (right).

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A physicist’s approach to SRS treatment planningPresenter: Ian Paddick, MSc MIPM CSci Consultant Physicist

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nuclear medicine 17

Novel radiotracer evaluated in humans

082416

The enzyme phosphodiesterase-2A (PDE2A) is an important target in the development of drugs to treat patients with cognitive impairments. A PDE2A PET tracer could enable eval-uation of disease-specific changes and testing of candidate compounds. Now, researchers from Yale School of Medicine, in collaboration with Pfizer, have reported the first in-human assessment of the radiotracer 18F-PF-05270430 – the fi rst PET ligand to exhibit good properties for imag-ing and quantifying PDE2A in vivo.

After evaluating the safety and tol-erability of 18F-PF-05270430 in six healthy male volunteers, and exam-ining appropriate analytic strate-gies for tracer binding to PDE2A sites, the researchers reported that the radiotracer shows promise as a PDE2A PET ligand ( J. Nucl. Med. doi: 10:10.2967/jnmed.115.166850).

The team had previously evalu-ated the radiotracer in lab monkeys. This showed that 18F-PF-05270430 is a potent PDE2A inhibitor with high binding affinity, excellent selectiv-ity over other phosphodiesterase enzymes (PDEs) and good PET imag-ing properties (J. Med. Chem. 56 4568).

Prior to conducting their experi-ment with humans, lead author Mika Naganawa and colleagues

administered the radiotracer to four rhesus monkeys for radiation dosim-etry. They acquired PET images in a sequence of 14–17 passes in four- or five-bed positions and computed mean organ activity values to form time-activity curves. They deter-mined that the gall bladder had the highest radioactivity uptake, fol-lowed by the liver. The dosimetry study provided an effective dose of less than 0.30 mSv/MBq. Based on

this study, a human target dose of below 185 MBq was selected.

Each human volunteer injected with the radiotracer had two PET scans performed four to five days apart. After an analysis of the initial data, the acquisition duration was shortened from 240 minutes for the fi rst three volunteers to 120 minutes for the other three. None of the volun-teers experienced any adverse events. The researchers reconstructed

dynamic scan data. Blood samples were taken to determine whole blood activity and the metabolite-corrected plasma input function.

Nine brain regions of interest were studied, including the stratum, white matter, neocortical regions and the cerebellum. The cerebellum was selected as a reference region to cal-culate binding potentials. The highest uptake was seen in putamen, caudate and nucleus accumbens, followed by cortical regions and cerebellum. The cerebellum showed the lowest uptake, and the authors noted that a blocking study in humans is needed to validate its suitability as a reference region.

The team used a variety of mod-elling methods to calculate volume of distribution and binding poten-tials. Regional time-activity curves were well fi t by multilinear analysis 1 (MA1) when arterial data were available. A 70 minute scan duration required to satisfy stability criteria for MA1 was suffi cient to quantify the volume of distribution and bind-ing potentials. The study showed that MA1 was the most suitable model for describing the kinetics.

Looking ahead, Naganawa and colleagues noted that “noninvasively imaging PDE2A enzymes could be used to facilitate the development of

PDE2A inhibitors. This technique enables the capability to quantita-tively measure PDE2A enzyme occu-pancy levels of drugs, a prerequisite for expression of PDE2-mediated phar-macology and target modulation.”

Principal investigator Richard E Carson told medicalphysicsweb that the radiotracer will be useful as a research tool in clinical research as well as for evaluating changes in PDE2A in patients with cognitive disorders such as schizophrenia and Alzheimer’s disease.

“PDE2A is an important target in drug development for treatment of cognitive impairments,” he said. “In preclinical models, PDE2A inhibi-tors exhibit memory and cognitive enhancement properties, so PDE2A inhibitors are being developed as an adjunctive therapy to antipsychot-ics for the treatment of the cogni-tive impairments associated with schizophrenia. The radiotracer 18F-PF-05270430, combined with appropriate tracer kinetic model-ling, allows us to measure occupancy at PDE2A by potential new drugs. In this way, the dose of the drug can be optimized to provide suffi cient occu-pancy of the enzyme to have its bene-fi cial effects, and to avoid overdosing patients to minimize side effects.”

Tracer imaging: MR and co-registered typical PET images in test and retest conditions (10–60 min post-injection of 18F-PF-05270430).

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photoacoustic tomography 19

Phantom targets quantitative imagingPhotoacoustic tomography – a non-invasive modality based on laser-generated acoustic waves – is of great interest for biomedical applications, combining the fi ne spatial resolution of ultrasound with the spectroscopic specificity of optical techniques. Quantitative photoacoustic tomog-raphy (qPAT), meanwhile, maps the optical absorption over a series of wavelengths to create high-reso-lution 3D maps of the distribution and concentration of tissue chromo-phores, such as oxyhaemoglobin, deoxyhaemoglobin, lipids and water.

This quantitative information could enable applications like hypoxia measurements in pre-clinical studies of tumour regions, functional brain imaging by tracking oxygen satu-ration, and lipid mapping for diag-nosis and staging of atherosclerotic plaque. Currently, however, there are no phantoms available for validation of qPAT systems and reconstruction algorithms, so little validation work has been described in the literature, despite claims that photoacoustic imaging can be used for quantitative measurements of, for example, blood oxygenation. To remedy this short-fall, UK researchers have investigated the use of polyvinyl chloride plastisol (PVCP) to create a qPAT phantom (Phys. Med. Biol. 61 4950).

“There has been an extensive body of theoretical work to solve the quan-tifi cation problem in photoacoustics. Despite the success of these methods in theory and simulation, they have

mostly not been tested experimen-tally,” said Martina Fonseca from University College London. “Experi-mental validation and optimization of qPAT frameworks is an essential step-ping stone if they are to be successfully applied in pre-clinical and clinical studies. Having a stable, long-lasting phantom with tissue-realistic opti-cal and acoustic properties is essen-tial when trying to implement qPAT beyond pure simulation studies.”

Material mattersAn ideal phantom material for pho-toacoustic imaging must have tissue-realistic and controllable acoustic and optical properties, tissue-realistic thermoelastic properties, a versatile architecture, photo- and mechanical stability, and reproducible fabrica-tion. For qPAT, additional require-ments include a well-characterized frequency dependency of sound speed and acoustic attenuation, and embeddable absorbers with unique spectra similar to those of biological tissue chromophores.

To meet these requirements, Fon-seca and colleagues proposed PVCP, which offers long-term stability, optical transparency and tissue-like acoustic properties. They performed a series of tests to assess its suitability.

First, they assessed the frequency-dependent sound speed of PVCP up to 20 MHz and acoustic attenuation up to 15 MHz. While both param-eters were comparable to tissue-like structures, sound speed was about 10% lower than the typical soft-tissue range (1450 ms–1 for fat, for example, or 1590 ms–1 for liver). Acoustic atten-uation at 1 MHz (0.6–1) was within the tissue range, though greater than desired at higher frequencies. Meas-urements of soft, medium and hard PVPC samples (created by adding a softener agent) showed that harder samples had increased sound speed and attenuation.

PVCP has intrinsic, relatively low optical scattering that can be increased towards more tissue-like levels using optical scatterers such as TiO2 powder. The researchers fab-

ricated soft PVCP samples with four TiO2 concentrations and measured the reduced scattering coefficients and intrinsic absorption coeffi cients at 400–2000 nm.

The reduced scattering was suc-cessfully tuned to tissue-equivalent levels, showing approximate linear-ity with increasing TiO2 concentra-tion. Up to 1000 nm, the intrinsic absorption was similar in magnitude to typical tissue background levels, with higher absorption peaks above 1000 nm.

PVCP absorption can also be tuned using additives. The researchers characterized the absorption of three pigment-based absorbers dispersed in PVCP. All three absorbers exhib-ited unique optical spectra and lin-ear absorption with concentration, favouring their use as endogenous chromophore analogues.

As photoacoustic imaging is per-formed using pulsed illumination with high peak powers, Fonseca and colleagues studied the absorption of the pigments at higher power. The resulting photoacoustic spectra dif-fered from the continuous-wave-based characterization, particularly for the red absorber. A five-fold variation in peak power led to up to about 13% variation in absorption coeffi cient. This is a worst-case sce-nario of direct pigment irradiation, however, and for a more realistic phantom with absorbing inserts at greater depth, the variation is likely to be much less pronounced.

To test the manufacturing feasi-bility, the researchers created three soft PVCP phantoms, including: a sub-500 µm wide line of self-adhe-sive black vinyl fi lm; a “UCL” pattern made of self-adhesive black vinyl fi lm; and a pair of 2 mm thick soft PVCP square inserts with black pig-ment. Photoacoustic images of the phantoms clearly revealed the main features in all phantoms.

They also created a phantom with two 1 mm diameter wall-less channels fi lled with absorbing solu-tions (copper chloride and nickel chloride). Multiwavelength pho-toacoustic images showed distinct absorption spectra for the two chan-nels. “Channels are a good analogue for blood vessels,” explained Fonseca. “Also, having two channels allows us to create a scenario analogous to the presence of an artery (with higher oxygen saturation) and a vein (with higher oxygen saturation), by inject-ing mixtures with different ratios of two dyes in each channel.”

The authors concluded that PVCP has potential as a useful and versatile qPAT phantom material but that, for now, its use may be limited to lower frequency systems. They are now working on experiments to obtain 3D, high-resolution quantitative maps of chromophore concentrations with high levels of accuracy and robust-ness. “I myself am working on acquir-ing experimental datasets that can be used to test and optimize theoretical qPAT frameworks,” added Fonseca.

Tuning the absorption: blue, black and red pigments dispersed in PVCP exhibit unique optical spectra and linear absorption with concentration.

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biomedicine����21

Scaffold maps cardiac cell activityResearchers at Harvard University have fabricated a flexible nanoelec-tronics scaffold that can house car-diac cells and map and modulate their electrical activity. The new platform could be used to follow pro-cesses such as ischemia in the heart, as well as to monitor and stimulate cardiac activity following surgery.

“Within our nanoelectronics scaf-fold we have an array of large num-bers of sensing devices that allow us to map the electrical behaviour/beat-ing of cardiac cells in 3D,” explains team leader Charles Lieber. “The fast response time of the scaffold means that we can obtain data with sub-millisecond time resolution – which greatly exceeds the capabilities of optical methods.”

“The sensing device enables us to study things like arrhythmia in car-diac tissue and how effective drugs are against heart disease,” he adds.

Measuring drug efficiencyThe researchers made their scaffold using a simple and scalable photoli-thography bottom-up approach (an

industry standard for fabrication). They first printed silicon nanow-ires into a polymer thin film surface and then photolithographically pat-terned the surface to define the spots of the final device arrays. Next, they used photolithography to define the lower layer of the (SU-8) polymer mesh network and then put the elec-trical “wiring” on top of the poly-

mer mesh to connect the nanowire devices to input/output connections. Lastly, a photolithography step was used to define a top layer of polymer mesh that matches the lower mesh layer and encapsulates all the metal lines, but which leaves the nanowire devices open.

The team attached its scaffold to a modified Petri dish for cultur-

ing rat ventricular cardiomyocytes. The electrical activity of cells was measured over a period of eight days. Extracellular cardiac action potential signals recorded from 4 × 4 sensors in a single layer across a 5 × 5 mm2 domain show a synchro-nized heart beating rate of 1.8 Hz, an amplitude of 1–2 mV and a peak width of around 1 ms from all 16 channels.

Over the course of the experiment, beating frequency decreased but the researchers were able to tune this up by applying norepinephrine (a stress hormone). They can also down-modulate the speed action potential transmitted by applying heptanol (a blocker of gap junctions that connect cardiomyocytes).

“Such ‘smart’ control of cardiac activity is possible because we receive continuous feedback from the cul-tured tissue,” says Lieber. “The fast 3D mapping possible with the device allows us to trace how cardiac tissue behaves in disease models or when certain drugs are administered. Such work could help advance fundamen-

tal research on the heart and even help pharmaceutical companies to screen the effectiveness of drugs.

The simultaneous mapping and regulation of cardiac activity we have demonstrated in our research could also potentially lead to preci-sion medicine and novel ‘electronic therapies’,” he told our sister site nanotechweb.org.

The researchers, reporting their work in Nature Nanotechnology doi: 10.1038/nnano.2016.96, say that they are now particularly excited about implanting their nanoelectronics-cardiac tissue patch into animal models of heart disease. “We are also extending the concept to other tis-sues, including blood–brain barrier tissue models that could allow us to investigate viral infection in the brain in a truly unique way,” says Lieber. “It might also be interesting to extend the functionality of the device by incorporating biochemical and pres-sure sensors into it.”

Belle Dumé is contributing editor of nanotechweb.org.

Flexible scaffold: team member Xiaochuan Dai holds a nanoelectronic cardiac patch in front of the laboratory measurement electronics.

A 3D artificial scaffold network made from multi-walled carbon nanotubes (MWCNTs) could help locally “rewire” nerve tissue. This is the new finding from researchers in Italy and Spain, who say that the technology could be exploited as a neural interface to help repair nerve fibres after injury or disease (Science Advances 2 e1600087).

The central nervous system has an inherent ability to regenerate itself and new carbon nanotube scaffolds could be used to help this process along. “Indeed, previous research by our group has already shown that carbon-based nanostructures, such as MWCNTs, can support neural growth and the formation of syn-apses,” explain team leaders Laura Ballerini of the International School of Advanced Studies (SISSA) in Tri-este, Italy, and Maurizio Prato of the University of Trieste.

“In this new work we have used, for the first time, a 3D MWCNT self-standing framework as a tissue scaf-fold to interface spinal cord explants from rats,” Ballerini told our sister site nanotechweb.org. “We found that such materials can guide central nervous system reorganization in 3D, leading to the formation of a dense hybrid tissue that looks like a knotted tangle of tubes.”

The team showed that when scaf-folded to spinal segments segregated by a MWCNT bridge, webs of nerve fibres (that had sprouted from the segments in culture) spontaneously form. These webs “invade” the nano-

tube scaffold and intertwine with it.To study how biocompatible their

system was, Ballerini and colleagues implanted small portions of pure 3D MWCNTs into the brains of rats for four months. After an initial, and normal, inflammatory response to the material, none of the animals developed any further adverse tis-sue reactions. This suggests that the CNT structure can safely integrate into nerve tissue.

“These excellent results at the structural and functional level in vitro and in vivo showed biocompatibility and are encouraging us to continue this line of research,” says Ballerini. “These materials could be useful for covering electrodes used for treating movement disorders like Parkinson’s because they are well accepted by tis-sue, while the implants being used today become less effective over time because of scar tissue. We hope this encourages other research teams with multidisciplinary expertise to expand this type of study even further.”

Nicholas Kotov of the University

of Michigan in the US, who was not involved in this research, says that this is a “great paper”. The research-ers are tackling a difficult problem of “re-wiring” severed parts of spi-nal cord, he explains. “They present convincing results and in a few years it could be possible to direct the growth of neurons with meshes of carbon nanotubes.”

Charles Lieber of Harvard Univer-sity, who was not involved either, adds: “this work is an exciting exam-ple of using 3D mesh architectures based on nanomaterials for ena-bling new opportunities in tissue engineering. The authors use of carbon nanotube meshes to guide the growth of neurons in 3D is very interesting from both a basic science perspective and offers unique oppor-tunities in regenerative medicine.”

Ballerini and colleagues are now busy trying to exploit nanomaterial-based scaffolds like the one described here to develop a new therapeutic platform to regenerate the central nervous system.

Nanotubes aid in nerve repair

The overuse of antibiotics gives harmful bacteria the opportunity to evolve into drug resistant strains that threaten healthcare. To help tackle the problem, scientists in China have begun a pilot study examining biomarkers exhaled by patients. The team’s goal is to develop an efficient (fast, accurate, painless and afford-able) test that will assist doctors in prescribing antibiotics only when the treatment is absolutely necessary.

Reporting their first results in Jour-nal of Breath Research, the researchers based at Zhejiang University have used benchtop analytical methods as a stepping stone towards developing future diagnostic tools ( J. Breath Res. 10 027102).

The group is focusing its initial work on ventilator-associated pneu-monia patients in the intensive care unit. Here, it is critically impor-tant to differentiate between life-threatening bacterial infection and common colonization to avoid pre-scribing antibiotics unnecessarily. “To confirm whether patients have a bacterial infection of the respiratory tract, doctors currently have to take a number of different samples (blood and sputum), and even chest X-rays in the case of pneumonia,” explained Kejing Ying, who is coordinating the work and is based at the Zhejiang University School of Medicine.

Breathe in, breathe outAnalysing samples from 60 vol-unteers, the scientists have found a potentially useful link between

the presence of exhaled acineto-bacter baumannii derived volatile organic compounds (VOCs) and patients diagnosed with bacterial pneumonia.

“The challenge we face is that many VOCs are not unique to one pathogen,” added Ying, who is work-ing with colleagues at Zhejiang Uni-versity’s Department of Biomedical Engineering.

Ultimately, the team hopes that its research will lead to an approved non-invasive test to provide early warning of bacterial infection in the lower respiratory tract.

Breath test could help reduce over-prescription of antibiotics

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Three-dimensional mesh: the carbon nanotube sponge structure.

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Project leader: Kejing Ying is based at the Zhejiang University School of Medicine.

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22 focused ultrasound

Implant helps deliver drugs to the brainBrain diseases are notoriously diffi-cult to treat due to the blood–brain barrier (BBB), a protective layer of cells limiting the delivery of most drugs into the brain. One promis-ing approach for BBB disruption combines pulsed ultrasound with injected microbubbles, which vibrate in response to these sound waves, to temporarily open the BBB.

CarThera, a French start-up based at the Brain and Spine Institute at Pitié-Salpêtrière Hospital, is devel-oping the SonoCloud device, an implantable ultrasound transducer that is fixed to the skull. The device has no internal energy source, mak-ing it MRI-compatible, and is instead powered externally via a transcuta-neous needle that’s only connected during treatment sessions.

Alexandre Carpentier, CarThera’s founder, inventor of SonoCloud and a neurosurgeon at Pitié-Salpêtrière Hospital, and collaborators have now tested the device in patients with recurrent glioblastoma, an aggressive and difficult to treat brain tumour. Preliminary results indicate that the device can safely disrupt the BBB and boost the amount of drug delivered to

the brain (Sci. Transl. Med. 8 343re2). “The blood–brain barrier is one of

the last major frontiers of neurosci-ence,” said Carpentier. “The publica-tion of the trial results in one of the most prestigious US scientific jour-nals is a major acknowledgment of this medical first.”

The researchers implanted Sono-Cloud devices within the skulls of 15 patients, in areas overlying the tumours. In a dose-escalating phase

1/2a trial, the BBB of each patient was transiently disrupted at monthly treatment sessions using pulsed ultrasound and systemically injected microbubbles.

The first three patients were treated at an acoustic pressure of 0.5 MPa. Patients in the second cohort started at 0.65 MPa, with intrapatient dose escalation at subsequent sonications up to 0.95 MPa. Patients in the third, fourth and fifth cohorts started at

acoustic pressures of 0.8, 0.95, and 1.1 MPa, respectively, with dose escalation up to 1.1 MPa. In total, 41 sonications were performed in the 15 patients. All sonication cycles were followed by systemic infusion of carboplatin.

Preliminary successContrast-enhanced MR images revealed that no BBB disruption was achieved in patients receiving treat-ments at acoustic pressures of 0.5 or 0.65 MPa. Overall, BBB disruption was observed in 28 of the 41 sonications – eight of 11 sonications at 0.8 MPa, six of seven sonications at 0.95 MPa, and all 14 sonications at 1.1 MPa – without detectable adverse effects.

The trial is still ongoing, as the maximum tolerated ultrasound dose has not been reached. How-ever, data to date are sufficient to infer that transient BBB disruption with the SonoCloud system can be achieved with a threshold pressure dose of 0.8 MPa. Preliminary find-ings indicate that the approach is safe and well tolerated in patients with recurrent glioblastoma and has the potential to optimize chemo-

therapy delivery in the brain.T he researchers note that,

although the trial’s primary objec-tive was not to assess treatment effi-cacy, in nine patients with confirmed BBB disruption, the region encom-passed by the ultrasound field had no detected tumour progression on MRI. If efficacy holds up in further trials, the technique may offer a new treatment strategy for patients with brain cancer and potentially also neurodegenerative disorders.

“The publication of this scientific paper supports the SonoCloud con-cept. It will allow us to start working on subsequent clinical developments with a view to marketing the device,” said CarThera’s CEO Frédéric Sot-tilini. “We plan to raise money in 2017 to fund a large-scale phase 2b/3 clinical trial in 200 patients, with centres in Europe and the US. SonoCloud could be commercially available in 2020 for use in recurrent glioblastoma, with CE marking and FDA approval obtained in the mean-time. At the same time, the company will carry out exploratory studies in other indications, including Alzhei-mer’s disease.”

Researchers from the US have iden-tified a correlation between the transmitted infrared intensity and ultrasound time-of-flight across ex vivo human-skull specimens. This finding may pave the way toward a simple and low-cost method for aberration correction in therapeu-tic and diagnostic transcranial ultra-sound applications (Biomed. Phys. Eng. Express 2 035016).

Most commonly used to monitor blood f low in central areas of the brain, transcranial ultrasound is being investigated for use in a vari-ety of therapeutic and diagnostic applications – including brain imag-ing, targeted drug delivery (through the opening of the blood–brain bar-rier), and treatments of conditions including brain tumours, epilepsy and Parkinson’s disease.

The application of transcranial ultrasound does however come with some challenges. Firstly, the cranial regions that can be success-fully penetrated by ultrasound can often vary between different skulls, and these windows must be identi-fied. At the same time, to be coher-ently focussed, phase correction is typically required in order to offset the strong wave distortions gener-ated as ultrasound passes through the skull. A variety of approaches for this have been proposed by researchers, including time-rever-sal techniques, the insertion of a scattering source or a receiver into the brain, and CT-based or MR-

based model corrections. In a new study, Qi Wang and

colleagues at the Cleveland Clinic Lerner Research Institute explored the relationship between transmit-ted ultrasound and optical data. The team took measurements on nine ex vivo samples: two half-skulls and seven skullcaps. They illuminated various points on the interior of each specimen using a diffuse infrared light source, and then measured the light transmitted to the skull’s outer surface. Similarly, acoustic measure-ments across the skulls were taken within a water tank, recorded using a needle hydrophone.

The researchers found a positive correlation between the intensity of infrared light transmitted through the skull at a given location with the time it takes sound to travel through the skull. A plausible explanation for the finding, Wang says, might lie in how skulls are composed of layers of spongy trabecular bone sandwiched

between layers of cortical bone, which is more homogeneous. The irregular nature of trabecular bone results in both increased light scatter and reduced sound speed compared with cortical bone.

While cautioning that there are still challenges ahead toward applying this method to practical ultrasound aberration correction, Wang says that “the big advan-tage of our approach over existing methods, such as CT-based or MR-based correction, would be its leap forward in terms of simplicity and convenience.”

“This method is completely non-invasive and one can easily imag-ine its clinical application. This is a great step forward for transcranial ultrasound focusing,” says Adrian Wydra, a medical physicist at True Phantom Solutions (formerly of the University of Windsor), who was not involved in this study.

Portable and economicalHighlighting the feasibility of the approach demonstrated by these init ia l exper iments, Kul ler vo Hynynen – a medical physicist at the University of Toronto – agrees, adding: “The method is especially promising since it could be port-able and low cost, making trans-skull therapy and imaging feasible outside of major medical centres.”

The researchers are now moving to explore the potential for using backscattered infrared for the same purpose. And at the same time, they are looking to optimize the optical parameters in order to use the technique for making analyses through skin.

The SonoCloud inventor: Alexandre Carpentier, a neurosurgeon at Pitié-Salpêtrière and founder of CarThera, holds the implantable device.

IR light reveals acoustic speed

Light transmission: a heat lamp was used as the light source to illuminated each skull sample.

INSIGHTEC’s Exablate Neuro sys-tem has received FDA approval for non-invasive treatment of essen-tial tremor (ET), the most common movement disorder, in patients who have not responded to medication. The Exablate Neuro uses focused ultrasound to precisely target and ablate tissue deep within the brain with no incisions or implants. Treat-ment is performed under MRI guid-ance to enable real-time monitoring. The treatment, which carries mini-mal risk of infection, bleeding or other surgical complications, is per-formed during a single session with no anaesthesia, allowing patients to quickly return to normal activity.

This FDA approval was based on data from a randomized, double-blind, multi-centre clinical study designed to evaluate the safety and efficacy of non-invasive thalamot-omy with MR-guided focused ultra-sound. A total of 76 patients were enrolled in the study and randomly assigned to receive Exablate treatment

(56 patients) or a sham procedure (20 patients) without any ultrasound energy. Patients in the placebo arm were later allowed to undergo an Exablate Neuro treatment.

Patients treated with the Exablate Neuro showed almost 50% improve-ment in their tremors and motor function three months after treat-ment, compared to their baseline score. Patients in the control group had no improvement. A year later, patients who underwent the Exab-late Neuro procedure retained a 40% improvement in these scores com-pared to baseline.

“The results show that Exablate Neuro is safe and effective for treat-ing essential tremor. Finding the most effective way to manage tremor symp-toms is crucial for patients. Those we have treated show immediate tremor control, allowing them to regain the ability to perform daily tasks such as eating and writing,” commented principal investigator Jeffrey Elias from the University of Virginia.

Exablate Neuro approved for ET

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Scalpel-free approach: Jeffrey Elias led an international trial examining the use of MR-guided focused ultrasound to treat essential tremor.

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