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SPECT has been used to detect Par-kinson’s disease with 98% accuracy using a quantitative, automated analysis based on machine learning. Developed by Portuguese research-ers and validated using brain images from 654 individuals, the approach outperformed visual analysis and other automated techniques in the literature, and can enable more appropriate and timely treatments for patients ( J. Neural Eng. 12 026008).

Miguel Castelo-Branco and Fran-cisco Oliveira of the University of Coimbra applied their technique to iodine-123 labelled FP-CIT SPECT, a popular tool in the diagnosis of Parkinson’s disease. In the scans, decreased uptake of the cocaine analogue in the brain’s striatum indi-cates an absence of the dopamine transporters to which the tracer would otherwise bind in disease-free individuals. Images are used to exclude conditions including essen-tial tremor. However, in some cases, especially those with early stage Par-kinson’s, changes in uptake can be difficult to detect by eye.

Algorithm learns from imagesThe new approach uses support vec-tor machines, a popular machine learning technique. It uses an algo-rithm trained with a set of images of known status, where each is char-acterized by a set of pre-selected quantitative features. Each image voxel contained in striatal volumes-of-interest (VOI) on the left and right side of the brain constitutes a feature.

The “learning” algorithm identifies the mathematical model – in effect a boundary – that best separates images from individuals with Par-kinson’s disease and those without. Applied to an image of unknown status characterized using the same features as in learning, it classifies the image into one of the two groups.

Rather than use counts or uptake ratios, the approach analyses bind-ing potentials derived from each striatal voxel, which are a function of the number of dopamine transport-ers it contains. It equals the counts in that voxel – that are specifically from tracer molecules bound to dopamine transporters – normalized to the mean counts per voxel in a reference VOI. The reference VOI contains no dopamine transporters and there-fore no transporter-bound tracer. The parameter is a robust measure that varies less than other uptake parameters with factors such as the choice of reconstruction algorithm

and attenuation correction method.To validate their approach,

Castelo-Branco and Oliveira used scans from 209 controls and 445 individuals with early-stage Parkin-son’s disease. The images were from the Parkinson’s Progression Markers Initiative (PPMI), an international observational clinical study with the largest dataset of its kind.

Two fixed-size striatal VOI were applied to each image. They were placed at the same anatomical loca-tion each time by registering the images to a template, composite image constructed from multiple normal brain images in which the two VOI had been aligned.

Robust techiqueThe researchers trialled the approach for several permutations of the tech-nique, varying aspects including the registration algorithm, testing both rigid and affine algorithms, with the reference VOI location used to calculate binding potentials. The variations made little difference to classifier accuracy, which ranged from 96.5% to 97.9%.

There was also little change in accuracy when the number of images used to train the learning algorithm was varied, from 327 to 624 images, demonstrating that the technique is robust. Supporting the findings, subsequent, unpublished tests by the researchers using other, smaller image datasets have produced simi-lar accuracies, as have different

reconstruction and attenuation cor-rection methods.

“Based on our results, and also the results from other research groups, we think that it is time for the phy-sicians to give more importance to multivariate analysis-based meth-ods, which can be a powerful com-plement to the visual analysis or the simple commonly used uptake ratios,” said Castelo-Branco.

Both visual and computer-aided assessments of I-123 FP-CIT scans are recommended by the European Association of Nuclear Medicine Neuroimaging Committee. An approximate accuracy of 91% has been reported in the literature using visual assessments.

The researchers are developing similar approaches to detect other neurodegenerative condit ions including Alzheimer’s and Hunting-don’s diseases and plan to apply their technique to PET images using other tracers.

Jude Dineley is a freelance science writer and former medical physicist based in Sydney, Australia.

In association with the journal Physics in Medicine & Biology Issue 2, 2015

medicalphysicsweb review

Automating Parkinson’s diagnosisMachine learning method diagnoses Parkinson’s disease from SPECT scans with 98% accuracy.

“We think that it is time for physicians to give more importance to multivariate analysis-based methods.”

Key comparisons: images of mean binding potentials reveal higher tracer uptake for the control group (left) than for the Parkinson’s disease group (centre). The right-hand images show t-values of a Student’s t-test.

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radiotherapy����3

VMAT technique spares hippocampusFor patients with multiple brain metastases, the benefits of whole-brain radiotherapy include the relief of neurological symptoms and improved local disease control fol-lowing surgery and radiosurgery. However, irradiation of the hip-pocampus to the typical 30 Gy pre-scription can result in memory loss and a consequent drop in quality-of-life, motivating the development of treatment techniques that spare the structure.

In new work, researchers in the US have devised a class solution that rapidly generates volumetric-modulated arc therapy (VMAT) plans with substantially lower dose to the hippocampus than delivered by conventional whole-brain plans. The technique, whose develop-ment was led by Wolfgang Tomé of the Montefiore Medical Centre and Albert Einstein College of Medicine in New York, spares the hippocam-pus and other sensitive structures while delivering sufficient dose to the rest of the brain. In their retro-spective study, Tomé and co-authors successfully implemented the tech-nique in 20 patients (Med. Dosim. doi:

10.1016/j.meddos.2014.11.007).The research was motivated by the

upcoming NRG-CC001 and NRG-CC003, randomized phase III and phase II/III clinical trials that will evaluate the benefits of hippocam-pal avoidance. The trials follow on the back of the RTOG-0933 phase II single-arm trial. Using mainly intensity-modulated radiotherapy (IMRT) and helical tomotherapy, this study reported a 7% decline in patient’s memory scores, signifi-cantly less than a 30% decline seen in a historical control treated with no hippocampal avoidance.

Planning schemeThough VMAT was permitted by the RTOG-0933 protocol, it was not used as often as anticipated, as dur-ing credentialing, participating cen-tres struggled to meet the protocol dose constraints using the technique. “We decided to work on a class solu-tion for VMAT planning that can be used by the community to arrive at VMAT plans that meet the dose con-straints in the follow-up studies to RTOG - 0933,” said Tomé, the medical physics co-chair for all three trials.

A key difference from other

h ippo c a mpa l - spa r i ng V M AT approaches is the division of the whole-brain planning target vol-ume (PTV) into four subvolumes. The approach enables optimization objectives that deliver uniform dose to a subvolume superior and inferior to a hippocampal avoidance vol-ume (the hippocampus plus a 5 mm margin). At the same time, objec-tives for the PTV that surrounds the hippocampal avoidance region in the axial plane are used to spare the structure.

A further unique characteris-tic is treatment delivery using two overlapping rotation arcs. With an isocentre placed in the centre of the hippocampal avoidance structure, one arc covers the superior section of the PTV and the hippocampal avoidance structure, while the other covers the structure and the inferior section. Collimator angles of 95° and 265° position the multileaf collima-tors (MLC) to move in the superior-inferior direction. “It allows the MLC to block the hippocampal avoidance regions without sacrificing the PTV coverage,” said Tomé.

A standard set of optimization

objectives was applied to each patient to meet the plan constraints chosen for the upcoming trials, which are the same as those used in RTOG-0933. They include a dose no less than 25 Gy to 98% of the PTV and a maximum dose to the hippocampus of 16 Gy, for a pre-scription of 30 Gy delivered over 10 fractions.

In 19 of the 20 patients, plans met the trial constraints after a single optimization. All plans were pre-pared in under an hour and passed a pre-treatment quality assurance test carried out using an electronic por-tal imaging device. Averaged over all patients, the maximum and mini-mum dose to the hippocampus was 15.7 ± 0.3 Gy and 8.5 ± 0.2 Gy respec-tively, substantially lower than the 30 Gy prescription received as part of the PTV during conventional whole-brain treatments.

Using the new technique, the NRG - CC0 01 and NRG - CC0 03 trials will start in the Northern Hemisphere in spring and autumn respectively, with at least 150 centres expected to participate in each, Tomé told medicalphysicsweb.

3D printing has been used for the first time to make anatomically accurate radiochromic dosimeters of small animals. Researchers in the US fabricated the plastic dosimeters from 3D printed moulds made using CT scans of a rat. Demonstrating high-resolution dose measurements accurate to within 3%, the phantoms will enable the verification of treat-ment plans used in preclinical stud-ies (Med. Phys. 42 846).

Stereotactic body radiotherapy (SBRT) in particular is set to benefit from this technique. Clinical studies have reported encouraging results from SBRT. However, mechanisms of tumour cell death are under debate and the most effective fractionation schemes are yet to be identified. MicroSBRT, where rats and mice are irradiated with fields as narrow as one millimetre, provides a way to test new treatments and investigate radiobiological response.

“Small animal SBRT treatment models can provide extremely valu-able insights into these questions, in order to achieve the full value of the SBRT promise,” said senior author Mark Oldham from Duke University.

Anatomically accurate dosimeters are the latest application of 3D print-ing in radiation oncology, where researchers have already fabricated customized bolus and phantoms with simple geometries. Oldham and his colleagues’ dosimeters are made of Presage, a transparent poly-urethane doped with leuco-dye.

Dose is derived from colour changes in the material that occur upon irradiation, measured using an optical CT scanner. The plastic has a linear dose response and is tissue equivalent, though attenuation can be increased by adding an iodine-based compound. Also a liquid, Pres-age is poured into a mould, where any shape can be used, then cured.

T he researchers made one homogenous, tissue-equivalent dosimeter and another containing a high-atomic-number spinal insert. The first was designed for 3D dose measurements and the second to enable X-ray cone-beam CT (CBCT) image guidance in a microirradiator, using the bone-mimicking anatomy.

Flexible polymer moulds of the body and spine were 3D printed using the segmented body surface and vertebral bodies in a 40 mm pel-vic section of a CT scan of a rat. To make the heterogeneous dosimeter, the spine insert was prepared first and positioned in the body mould, around which tissue-equivalent Presage was poured and cured.

Performance testingHaving established the feasibility of manufacture, the researchers tested

the ability of the dosimeters to verify a spinal microSBRT treatment that included 10 mm and 3 mm wide fields. X-ray CBCT was successfully used to align the inhomogeneous dosimeter, and once the carbon fibre treatment stage had been adjusted, the dosimeter was replaced with the homogeneous version for treatment delivery.

Dose recorded by the dosimeter, measured using a high-resolution optical CT system with 0.5 mm3 voxels, was accurate when compared against independent measurements. The isocentre dose deviated by 2.8% from a point measurement made with a nanocrystal scintillation detector developed at Duke Univer-sity. Differences of up to 3% were observed for the 10 mm field when compared to 2D radiochromic film measurements. In the 3 mm field, the dosimeter underestimated dose by 6.7%; the deviation is thought to have been caused by scattered light and is under further investigation.

“After nearly 10 years of research and development into 3D dosim-etry utilising Presage, we feel the techniques and abilities have now matured to a degree where quite remarkable feats of dosimetry are possible,” said Oldham of the findings.

In ongoing work, the research-ers are incorporating further inho-mogeneities into the dosimeters and enabling the conversion of dose measured in the homoge-neous dosimeter into that received by (heterogeneous) small animals upon delivery of the same treatment plan.

A new treatment that uses radio-active holmium microspheres to attack liver tumours has received the European CE mark, enabling its use in hospitals throughout Europe. Developed by the University Medical Center (UMC) Utrecht, the treatment is being marketed by UMC spin-off Quirem Medical. The therapy, also known as radioembolization, involves injecting microspheres loaded with holmium-166 into the hepatic artery, under image guid-ance. The microspheres become trapped in the smallest blood ves-sels in and around the liver tumours, thereby emitting their radiation close to the tumour. Several clinical studies are ongoing to investigate the technique’s efficacy.

“ We consider our holmium microspheres as ‘the next genera-tion of microspheres’,” said Quirem founder Frank Nijsen. “Treating liver tumours with yttrium microspheres is already a proven and valued cancer therapy. The new holmium micro-spheres constitute the next step in the development of this technology. Because they show up on MRI scans and SPECT-CT, these microspheres can be tracked, allowing custom-ized treatment for each individual patient.” The UMC researchers will now work with Quirem to adapt the approach for treating tumours in other organs, with research start-ing this year on the use of holmium microspheres on head-and-neck tumours.

Dose colour wash: the class solution resulted in uniform dose to the PTV superior and inferior of the hippocampus and sparing of the hippocampus. Reprinted from Medical Dosimetry.

3D printed: anatomically accurate dosimeters were produced from Presage radiochromic material.

CE certified: Maurice van den Bosch from UMC Utrecht, Jan Sigger, Quirem’s CEO, and Quirem’s chief scientific officer Frank Nijsen.

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proton therapy 5

Proton radiographs help predict range Proton therapy planning relies upon estimates of particle range in the patient, typically derived by con-verting Hounsfi eld units (HU) in an X-ray CT scan to relative stopping powers (RSP). This approach uses literature values of tissue composi-tion, however, and patient-to-patient variations can result in RSP errors of over 2%.

Addressing this, researchers at University College London (UCL), Massachusetts General Hospital (MGH) and IBA in Belgium have devised a patient-specific calibra-tion approach. Their strategy uses a proton radiograph to improve esti-mates of range that are quantified using water equivalent path lengths (WEPL) (Phys. Med. Biol. 60 1901).

“The ability to be able to more accurately predict WEPL will ulti-mately allow for tighter treatment planning margins and a greater sparing of normal tissues, reducing the toxicity and risk of secondary cancers to the patient,” said UCL’s Paul Doolan.

Proton CT can eliminate the need for calibration by providing 3D images of RSP directly, from which WEPL maps can be derived. How-ever, the technique is not in routine use. Unlike X-rays, protons undergo multiple Coulomb scattering events on passing through tissue, limiting spatial resolution. Prototype CT scanners are also expensive, bulky and could signifi cantly impact clini-cal workf low, if part of a clinical treatment gantry. As a more feasi-

ble alternative, Doolan and his col-laborators developed their hybrid approach. “Combining [2D proton imaging] with a high-resolution X-ray CT dataset allows us to com-bine the geometric, anatomical information from the CT and the RSP information derived from a pro-ton radiograph,” he said.

In the optimization, a WEPL map is derived from a proton radiograph taken in the planned direction of the therapy beam. The map is compared to an equivalent digitally recon-structed radiograph (DRR) created from the X-ray CT scan that also maps WEPL, rather than electron density. The DRR is generated by converting each voxel’s HU to RSP using a generic stoichiometric cali-bration. Proton energy losses along ray traces through the imaged vol-ume are then calculated.

The generic calibration curve is then adjusted to reduce the differ-ence between the two WEPL maps and re-applied to the X-ray CT data

to construct a new DRR. The pro-cess is repeated until the difference between the two maps, quantified using a cost function, is minimized.

Using digital phantoms with known compositions and simulated images, the optimizer produced significantly more accurate WEPL values than those obtained with the generic calibration. The improve-ment was also seen in experimen-tal measurements of two physical phantoms.

Developed by the MGH research-ers with support from vendor Sun Nuclear, a simple system compris-ing a 2D array of 249 semiconduc-tor diodes and the therapy beam as a proton source was used to acquire the radiographs. In a soft-tissue phantom, differences between WEPL maps generated from the calibrated X-ray CT data and directly from the proton radiograph were smaller after optimization. The root mean square error (RMSE) and mean difference were 2.9% and –0.2% with optimi-zation, compared to 3.6% and –2.1% using the generic calibration.

In a fi nal test, the optimizer pro-duced superior results when used to generate WEPL maps at a fi xed, typi-cal tumour depth in the same physi-cal phantoms.

In future work the collaboration plans to adapt the technique for use with a scanned pencil beam and incorporate a higher-resolution pro-ton detector. “We anticipate the fi rst patients could be imaged in two to three years,” said Doolan.

Beam tracking in scanned carbon ion therapy, where the pencil beam is steered in 3D to correct for tumour motion, can minimize the degrada-tion of dose distributions in the treat-ment plan upon delivery. However, there has been little investigation of the sensitivity of this approach to uncertainties in the movement of the tumour and the beam, motivating a study by a US-German collaboration (Phys. Med. Biol. 60 1717). “A major question in the fi eld has been how reliably such a system could perform in the presence of any imperfections from the simulated ideal case,” said fi rst author John Eley.

Using simulations in phantoms and patient CT scans, the collabora-tion assessed the impact of several sources of uncertainty on a tracking technique developed by senior author Christoph Bert and colleagues at the GSI Helmholtz Centre for Heavy Ion Research in Darmstadt. The technol-ogy, which is not yet in clinical use, corrects for tumour motion dur-ing irradiation using offsets derived from a pre-treatment 4D CT scan. An external tumour motion sur-rogate synchronises the beam with the tumour. The approach assumes the pre-treatment scan accurately represents tumour motion during treatment and that the correlation between the tumour’s motion and the surrogate is fi xed.

Two liver and two lung phantoms, each containing a 3 cm spherical tumour that moved sinusoidally were used in the simulations. For each, 4D

treatment plans using a single fi eld were generated for 18 motion cycles with varying periods and starting phases. The researchers compared the dose distributions for a single fraction delivery when the tumour was perfectly tracked, and when sev-eral errors, including phase delays and random errors, were deliberately introduced. The same uncertainties were introduced to a four-fi eld plan generated using CT scans of a previ-ously treated lung-cancer patient.

Technical uncertainties in beam delivery had little effect. An error of 0.5 mm resulted in a drop of less than 1% in V95, the volume receiving 95% of the prescribed dose. In contrast, phase delays caused dose coverage of the clinical target volume (CTV) to deteriorate signifi cantly. In the phan-toms, a 15° delay resulted in drops in V95 of up to 22% when averaged over the 18 motions, compared to when the beam tracked the tumour per-fectly. Similar drops were observed in the lung-cancer patient. In light of the fi ndings, systems that predict tumour motion during treatment or real-time tracking systems with motion detection loops shorter than 50 ms are needed to limit the effects, said Eley.

At present, the beam track-ing technology at Darmstadt can track tumours with complex 3D motions in anatomically realistic chest phantoms. With this latest research, it is moving closer to clini-cal implementation and potential commercialization.

Proton radiography: Paul Doolan and co-author Hsiao-Ming Lu.

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6 proton therapy

At the 3rd ESTRO Forum, held recently in Barcelona, Spain, Ray-Search Laboratories presented the latest advances in its RayStation treatment planning system. One important feature of RayStation 4.7 is the addition of multi-criteria optimization (MCO) for optimizing pencil-beam scanning proton ther-apy plans. MCO planning enables the dosimetrist and physician to make real-time trade-offs in plan objec-tives, simplifying the planning pro-cess while improving plan quality.

The company is currently also working with MedAustron in Aus-tria to create a clinical planning platform for carbon ion therapy. Ray-Search is developing a physical dose calculation for carbon ions, which will be combined with advanced biological models within the treat-ment planning system. “We have a working version of this software at ESTRO and the clinical release is targeted for the end of 2015,” Mark Mlyn, CEO of RaySearch Americas, told medicalphysicsweb.

Pencil beam scanning – moving a few millimetre sized beam to cover the target volume – represents the most advanced proton therapy delivery technique. The pencil beam, however, is unavoidably surrounded by a dose halo caused by scattering in the proton accelerator, the noz-zle and the patient’s body. To assess the resulting peripheral dose, Swiss researchers have used nuclear emul-sion films interleaved with tissue equivalent material to characterize the beam in the halo region ( JINST 10 P01007).

While previous studies have used small ionization chambers to assess the halo dose, the authors note that this study is the first to use emulsion films. “Nuclear emulsion films allow tracking of protons one-by-one and with high precision,” explained Saverio Braccini from the Univer-sity of Bern in Switzerland. “In par-ticular, each proton can be precisely localized and angular distributions studied. When studying the halo of a clinical pencil beam, the angular dis-tribution data revealed evidence that the halo is made of two components.”

Braccini and colleagues created emulsion films from a gel contain-ing silver bromide crystals, which form a latent track when traversed by an ionizing particle. After chemi-cal development, these tracks can be visualized using an optical micro-scope, with a spatial resolution of about 1 µm (the size of one silver grain) and an angular resolution of

a few milliradians.The team built a prototype pro-

ton detector comprising layers of the emulsion films (60 in total) interleaved with tissue-equivalent absorber material (polymethyl methacrylate). To evaluate the dose in a proton beam halo region, they irradiated the detector using Gantry 1 at the Paul Scherrer Institute (PSI), which delivered a 138 MeV proton pencil beam of about 8 mm FWHM. The total dose was about 6 Gy at the Bragg peak, which was located 116 mm into the detector (between films 50 and 51).

After irradiation and developing the films, the beam shape and halo could clearly be seen. The research-ers used automatic scanning systems to identify and count proton tracks

in the irradiated films (proton den-sity within 2 cm from the beam cen-tre was too high for the tracks to be reconstructed). They reconstructed proton tracks at various depths in the detector (different films) and meas-ured the track density in three areas close to the beam spot.

Plotting the number of proton tracks as a function of angle revealed two distinct components in the halo region. The first, which peaked at small angles and dominated at small depths, was almost parallel to the beam axis. The second component, which dominated at larger depths, was seen at larger angles and was attributed to proton scattering inside the detector’s tissue-equivalent material.

“By studying angular distribu-tions, we found evidence for the first time that the first component of the halo is almost parallel to the beam and is due to scattering in the accelerator and nozzle,” Braccini told medicalphysicsweb. “The second com-ponent is due to scattered protons inside the patient’s body, is charac-terized by large angles and largely dominates at depth. This second component gives the largest contri-bution to the dose given by the halo to surrounding tissues.”

As the second component can only be detected at greater depths, the authors note that for this detec-tor, the minimal depth that allows accurate dose estimation is 63 mm (the 31st film).

Determining the doseTo assess the dose delivered by each proton and thereby estimate the halo

dose, the researchers performed a GEANT4 Monte Carlo simulation of the experiment. As expected, the halo dose decreased with distance from the beam spot centre and increased with depth in the detector.

Examining individual emulsion films showed that film 1 (at 1 mm) only detected the first component, resulting in a measured dose of below 0.1 mGy. Films 31 and 40 (at 63 and 76 mm) were dominated by the second component and recorded higher dose values. The largest dose was recorded by emulsion film 41 (at 98 mm).

At distances of more than 25 mm, the maximum dose in the beam halo was less than 1.5 mGy for a central dose of 6 Gy. For a typical proton therapy fraction of 2 Gy at the Bragg peak, this equates to a halo dose of less than 0.5 mGy. To put this value into clinical context, the authors cite a recent planning study for prostate cancer treatment. For a proton plan with a mean target dose of 72.9 Gy, the mean dose to organs-at-risk ranged from 14.4 to 25.7 Gy. In com-parison, the extra dose delivered by the beam halo represents a negligible contribution.

“We are now working on apply-ing this technique to the detection of recoil protons due to neutrons, with the final goal of assessing the dose due to neutrons in particle therapy,” said Braccini. “Further studies of pro-ton radiography based on the angu-lar distribution of scattered protons are also underway.”

Tami Freeman is Editor of medicalphysicsweb.

Dose calculator lowers QA bottleneckIn proton therapy centres, treatment plans are commonly checked before the start of treatment by delivering them to a phantom on the treatment couch. However, such dose meas-urements are labour intensive, time consuming and unfeasible for use as part of a daily adaptive treatment regime – a goal of staff at the Paul Scherrer Institute (PSI) in Villigen, Switzerland.

In a move towards eliminating patient-specific measurements, researchers at PSI have developed an independent-dose-calculation (IDC) system for quality assurance of pen-cil-beam plans, as well as commis-sioning of treatment-planning and delivery systems. The IDC system enables 3D dose reconstruction at each step in the treatment workflow, from the generation of a fluence map by the treatment planning system (TPS), to treatment-plan delivery (Phys. Med. Biol. 60 2819).

“We hope that the IDC will help to improve the quality control chain, eventually allowing for rapid adap-tion of plans to changing anatomy, therefore improving the precision of fractionated proton therapy,” said

Gabriel Meier, first author and PhD student. “Recalculating a plan using the IDC takes less than a minute, and can be performed with the patient remaining in the treatment room.”

Targeted treatment QAWhile an important tool for check-ing treatment plans prior to deliv-ery, QA measurements provide no clue as to the source of differences in dose between them and the TPS. In addition to uncertainties in the dose calculation algorithm, errors can be introduced when TPS-generated flu-ence maps are converted into steer-

ing files that control the machine during treatment, and when treat-ment is actually delivered.

Addressing this, the IDC system calculates dose using data exported at each stage in the planning–treat-ment workflow, enabling targeted checks denoted by different levels. All levels use the same dose algo-rithm as the TPS. The approach was chosen to isolate workf low and technical errors from any algo-rithm-related uncertainties, as well as provide redundancy analogous to verification systems built into treat-ment-machine hardware.

Level 1 checks use the same field and beam data as the TPS to calcu-late dose, but in a separate software implementation. In doing so, they check the IDC performance against a clinically commissioned TPS that has been validated against treat-ment-machine measurements.

When the researchers compared the two systems, using four clini-cal head-and-neck plans previously delivered on PSI’s Gantry 2, they agreed to within ±0.3% in a voxel-by-voxel analysis.

Instead of relying on TPS field data, which include the position of each beam spot, Level 2 calculations derive field data from the steering files. In the files, spot positions are specified in terms of the sweeper magnet currents used by the treat-ment machine to steer the beam. The check enables the detection of errors introduced when the steering files are generated.

Comparing TPS and Level 2 cal-culations for the same four plans, Meier and his colleagues found voxel differences were all within ±2%. The differences reflect uncertainties in the IDC’s conversion of the sweeper-

magnet currents back into beam-spot positions, rather than genuine steering-file errors. The conversion relies upon a data fit, but the two parameters do not have a one-to-one relation.

Level 3 calculations use log files exported from the treatment machine that contain beam-spot positions, monitor units and beam characteristics actually delivered by the machine. In doing so, they retrospectively verify the delivered dose. In one of three Level 3 tests, the researchers performed checks of the first 107 fractions delivered to five patients on Gantry 2, and all frac-tions were confirmed as sufficiently accurate.

Level 2 and 3 calculations are already in clinical use at PSI in par-allel with existing QA tests to gain experience across a large number of clinical plans before eliminating the patient-specific measurements. In the longer term, the researchers plan to extend the IDC system to calculate dose with a different algorithm – a Level 4 calculation – to provide fully independent dose calculations that complement the other levels.

System calibration: an example IDC calculation for a patient agrees well with the dose predicted by PSI’s treatment planning system.

Reconstructed tracks: protons in the halo of a 138 MeV pencil beam traverse the film almost perpendicularly and appear as dots (image scale: 400 x 300 µm).

On show: RaySearch at ESTRO.

RaySearch adds MCO for protons

Films determine proton dose halo

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biomedicine����7

Bridging the gaps between disciplines Researchers in fields such as medical physics, biophysics and biomedical engineering are well served by tradi-tional journals. But for those working on the edges between disciplines or in interdisciplinary groups, the route to publication may be less clear cut. Enter Biomedical Physics & Engineering Express (BPEX)–the newly launched journal from IOP Publishing.

The aim of BPEX is not just to cover all three disciplines, but to focus on bridging the gaps between individ-ual areas, explained Founding Edi-tor Robert Jeraj from the University of Wisconsin-Madison. “Medical physics, biophysics and biomedical engineering have developed inde-pendently, but we are now realising that they have a lot of things in com-mon,” he said. “We are trying to bring these disciplines closer together, par-ticularly the intersections between them.”

One area that spans all three dis-ciplines for instance, is imaging. Within biophysics, this mostly con-cerns optical imaging and micros-copy, while imaging in medical physics involves clinical techniques, and biomedical engineering helps develop technologies for both. Another example is modelling, again

ranging from the cellular to the clini-cal level. The scope of the new journal is intended to be broad and inclusive, covering any application of physics and/or engineering in medicine and/or biology. “We’re aiming to provide a common ground for discussion between the disciplines,” said Jeraj.

As well as the Founding Editor, BPEX will have three Deputy Edi-tors, one from each discipline. Jeraj noted that while each Deputy Editor is a highly regarded expert in their own field, they were also selected as researchers able to see beyond these individual fields. “In order to be effec-tive in bridging between disciplines,

we also have to be very good within each discipline,” he explained.

One important goal of the new journal is to publish research with a broad geographical coverage. To drive this, the Editorial Board was created with members from all across the globe. “Researchers will feel more comfortable submitting to a journal where they can see con-nections with people they might know, or from their country,” Jeraj explained. “The Editorial Board is also tasked with identifying prom-ising groups and researchers within their regions, and encouraging them to come together and to feel at home

with BPEX.”Jeraj noted that in many coun-

tries around the world, the three disciplines that compose BPEX are less differentiated than in the USA or Europe. BPEX’s interdisciplinary model will particularly suit authors in such countries, for example, work-ing in a combined medical physics/biophysics department.

He also highlighted the situa-tion faced by researchers in lower-income countries, who may not have access to the latest state-of-the-art technologies. “Very often, people who don’t have financial resources compensate by being more innova-tive,” he said. “The research may not be really cutting-edge, but the ideas may actually be more innovative than those that just come from using advanced technology.”

“There are smart people every-where around the world,” he added. “This is a great way to bring them together and combine the most brilliant ideas in these disciplines from everywhere. I’ve already seen extremely high enthusiasm from groups around the world. They feel that the journal answers their needs by focusing on scientific rigour and innovation, not just on research

using expensive equipment.”One other key selling point of

BPEX lies in the “Express” in its title–which promises fast but rigorous peer review, with first decisions in less than 28 days on average. Jeraj notes that reviewers are given a rela-tively short deadline to respond.

BPEX also offers the option for transfer from IOP Publishing’s other journals, in cases where the paper doesn’t quite fit into a journal’s scope or is not deemed as interest-ing for that particular discipline. “If the paper is appropriate for BPEX, if it fits the scope and the criteria, and the authors agree to the transfer, then it goes on fast track,” Jeraj explained. “The original reviews are taken into account, which speeds up the publi-cation process and spares the referee pool.”

Looking ahead, Jeraj hopes that in five years’ time, BPEX will emerge as the key journal for interdiscipli-nary research. “The initial reactions that I’ve been getting have been extremely enthusiastic,” he told med-icalphysicsweb. “People think there is a real need for this interdisciplinary approach, especially for research that isn’t quite within one discipline or spans subject fields.”

Bringing disciplines together: BPEX’s Founding Editor Robert Jeraj.

A broad, inclusive, rapid-review journal publishing new research in all areas of biomedical engineering, biophysics and medical physics.

Free to read for 2015As part of the initial launch phase, all content in the journal will be free to read for individual users, universities and academic research institutes in 2015.

To find out more about publishing your work in BPEX, visit iopscience.org/bpex

BiomedicalPhysics & EngineeringExpressiopscience.org/bpex

NEW FOR 2015

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8 biomedicine

An interdisciplinary group of scien-tists in Lithuania has tested a com-plex tissue scaffold made by direct laser writing in vivo for the first time. The scaffold has exhibited high per-formance and biocompatibility, pav-ing the way for a clinical trial of the desirable tissue-engineering tech-nique (Biofabrication 7 015015).

Direct laser writing (DLW) is an advanced way of structuring mate-rials with light, without the use of a mask. Instead, a tightly focused laser beam scans a photosensitive mate-rial, creating a structure directly from a computer model. In this way it is like a 3D printer – but one with unmatched spatial resolution and material choice.

Since its introduction about a dec-ade ago, DLW has become a staple tool of many modern laboratories, crafting structures for use in micro-optics, nano-photonics, micro-flu-idics and various other disciplines. In principle, it could also herald a marked improvement in tissue engi-neering as a highly effective way of creating a scaffold in which cells can be grown and integrated with human tissue.

Cartilage cells, or chondrocytes, for instance, have already been shown to benefit from the 3D porous environ-ment of a scaffold, because such a scaffold resembles native cartilage. If chondrocytes could be effectively grown on a biocompatible DLW scaffold it would be good news for the many people who annually suf-fer osteochondral injuries – fractures

of the cartilage at the ends of bones.Despite the potential of DLW for

tissue engineering, complex struc-tures created by the technique have until now not been tested inside liv-ing organisms. “The manufacturing technique is quite sophisticated, and up to now only state-of-the-art set-ups worldwide can offer the required throughput in order to produce spec-imens for clinical experiments,” says laser physicist Mangirdas Malinaus-kas at Vilnius University.

That is why Malinauskas teamed up with materials scientists, manu-facturing technologists, biochemists and medics at various other Lithu-anian institutions to test a scaffold made from SZ2080, a hybrid organic-inorganic photopolymer consisting of organic acrylates and inorganic silicon and zirconium. DLW struc-

tured the scaffold, which was the size of a grain of rice, with a 3D net-work of micro-hexagons in which chondrocytes could be grown. The scientists implanted versions of the scaffold into rabbits, and removed them after one to six months to find out how much of the desired natural-like cartilage tissue remained.

The found that the scaffolds exhib-ited comparable biocompatibility to commercially available collagen membranes – a result that bodes well for studies with human cells and, eventually, clinical trials. “Currently this research is being performed, [and we are] hoping to obtain posi-tive results in the near future,” says Malinauskas.

Jon Cartwright is a freelance journalist based in Bristol, UK.

A novel, bacteria-repelling coating material that could increase the suc-cess of medical implants has been created by researchers. The mate-rial helps healthy cells “win the race” to the medical implant, beating off competition from bacterial cells and thus reducing the likelihood of the implant being rejected by the body (Biomed. Mater. 10 015015).

Implantation of medical devices into the human body has become an indispensable procedure in the treat-ment of major diseases. However, the failure rate of certain medical implants still remains high – around 40% for hip implants for example – due to the formation of biofilms when the implant is first inserted into the body. These thin films are com-posed of a group of microorganisms stuck together and can be initiated by bacteria sticking to the implant. This prevents healthy cells from attach-ing and results in the body eventu-ally rejecting the implant, potentially leading to serious complications for patients.

In their study, researchers from A*STAR (Agency for Science, Tech-nology and Research) in Singapore, Nanyang Technological Univer-sity and University of Hong Kong produced a material that not only repelled bacteria but also attracted healthy cells.

The base of the material was made from polyelectrolyte multilayers onto which a number of specific bonding molecules, called ligands, were attached. After testing various concentrations of different ligands,

the researchers found that the RGD peptide was particularly effective at inhibiting the attachment of bac-terial cells and attracting healthy cells, compared with collagen, when attached to dextran sulphate and chi-tosan multilayers.

This combination was tested on cultures of healthy fibroblast cells and cultures of bacterial cells, in which two specific strains were used – E. coli and S. aureus.

“The method we developed helped the host cells win the so called ‘race-for-surface’ battle, forming a con-fluent layer on the implant surface which protects it from possible bac-terial adhesion and colonization,” said lead author Vincent Chan, from Nanyang Technological University. “Medical implants currently have antibacterial silver coatings incor-porated into them; however, the total amount of silver used must be very carefully controlled because high concentrations could kill mamma-lian cells and become toxic to the human body.”

The bio-selective coatings devel-oped by Chan and co-workers do not have this problem as the materials used are non-toxic and preparation of the coating is a simple layer-by-layer process that uses water as a solvent. “At the moment this is just a ‘proof-of-concept’ study, so there is still a long way to go before the coat-ing can be used on implants in clini-cal setting. In future studies we hope to firstly improve the long-term stability of the coating,” explained Chan.

Virus mapped in 3D using X-ray pulsesIntense, extremely short pulses of X-rays have been used for the first time to reconstruct 3D images of individual virus particles. Developed by an international team of physi-cists, the diffraction technique could make it possible to map the structure of infectious viruses such as HIV, influenza and herpes, shedding light on possible ways to combat diseases caused by these infectious agents (Phys. Rev. Lett. 114 098102).

Scientists have used X-ray diffrac-tion to image live cells, viruses and simple nanostructures in 2D using a technique called nanocrystallog-raphy. This involves incorporat-ing a number of identical particles (viruses, for example) into a crystal – a time-consuming and expen-sive process that does not work for some particles. Now, a team led by Janos Hajdu at Uppsala University in Sweden has tested a technique that avoids crystallization with the added benefit of delivering 3D images.

The team focused on the Acan-thamoeba polyphaga mimivirus, which is about 450 nm across. The research-

ers injected virus particles into an aerosol stream, which was then sub-jected to high-energy pulses from an X-ray free-electron laser at Stanford University. Each pulse lasted just 70 fs and delivered a peak power density more than 1018 times that of sunlight hitting the Earth.

Such an extremely intense pulse will vaporize a mimivirus particle, but not before the X-rays scatter

from the virus and create a diffrac-tion pattern that is recorded by a bank of detectors. “We outrun radia-tion damage but we only get one shot per sample,” explains Hajdu. Because X-rays primarily scatter off electrons, the diffraction patterns that Hajdu and his team recovered can be used to calculate the dis-tribution of electrons within the mimivirus particles.

Hajdu and his team scattered X-rays off nearly 200 identical mim-ivirus particles, collecting one 2D diffraction pattern from each event. To make sure that the particles were not altered by being injected into an aerosol, the team showed that mimivirus particles that did not intersect the laser pulses were still infectious.

Adding a dimensionWith nearly 200 diffraction patterns in hand, Hajdu and his colleagues next set about adding the patterns together to produce a single 3D image. Combining data from differ-ent observations not only increases the signal – necessary for small viruses that scatter X-rays weakly – but also gives insights about viral structure that are only possible with 3D observations.

One important complication that the researchers had to overcome is that the particles were not all ori-ented in the same way with respect to the X-ray pulses. Instead, their orientations were randomly distrib-uted. Therefore, it was necessary to

retrieve the relative orientation of each mimivirus particle before add-ing the diffraction patterns together. Hajdu and his team did this using a mathematical optimization algo-rithm developed by another group of physicists in 2009. Because this algo-rithm presumes that the particles differ only in orientation, identical particles must be used. Fortunately, many pathogenic viruses that affect humans are reproducible, such as HIV, influenza and herpes.

The researchers achieved a spatial resolution of approximately 125 nm in their final reconstructed image of the mimivirus’s electron density. Bet-ter resolutions have been recorded in other 2D studies, but this investiga-tion is important because it shows that 2D diffraction patterns can be combined to produce 3D images of biologically important samples. “We now look forward both to pushing towards higher resolution and study-ing both smaller and larger samples,” says Hajdu.

Katherine Kornei is a science writer based in the US.

Diffraction patterns: images captured from 24 different virus particles.

Cell growth: SEM images of a collagen membrane (a, b) and a DLW scaffold (c, d) seeded with chondrocytes. While few chondrocytes are seen near the membrane surface, many are seen at every layer of the scaffold (white arrows). Scale bars: (a, c, d) 100 μm; (b) 50 μm

Tissue scaffold studied in vivo

Biomaterial improves implants

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Cell metastasis: environment mattersA cell’s ability to sense and interact with its local environment is impor-tant in both normal tissue develop-ment and progression of disease. Breast-cancer cells, for example, actively inf luence their environ-ment to induce matrix stiffening and encourage invasion into surround-ing tissues. In the quest to under-stand more about why cancer cells metastasize, researchers at Georgia Institute of Technology have per-formed a detailed study of the rela-tionship between matrix stiffness and cell characteristics.

The researchers studied two lines of metastatic tumour cells: MDA-MB-231 breast-cancer cells, which prefer rigid substrates, and SKOV-3 ovarian-cancer cells, which prefer compliant substrates. They cultured both cell lines on soft (2.83 kPa, sim-ilar to fatty tissue) and hard (34.88 kPa, similar to bone) gel substrates, as well as on a collagen-coated glass control, and assessed three impor-tant malignant characteristics: the cells’ ability to grow, to survive chemotherapy and to migrate (Phys. Biol. 12 026001).

“We recently discovered that ovarian cancer cells, which prefer-entially metastasize to a soft envi-ronment, become more aggressive when grown on soft gels – the exact opposite of breast-cancer cells, which often metastasize to stiffer environments like bone,” explained lead author Michelle Dawson. “We performed this study to understand this disparate behaviour and eluci-date the pathways responsible for the different mechanical preferences of ovarian and breast cancer cells.”

Dawson and colleagues first quan-tified cell proliferation on the three

substrates. They found that signifi-cantly less breast-cancer cells and more ovarian-cancer cells prolifer-ated on soft substrates, compared with hard substrates and glass. Ana-lysing cell viability after treatment with the anti-cancer drug doxoru-bicin revealed that breast-cancer cells on glass showed 20% higher viability over those on soft sub-strates. Ovarian-cancer cells were most resistant to doxorubicin on soft substrates.

To quantify the impact of rigid-ity on cell migration, the research-ers labelled cells with a dye to track cell motion. Breast-cancer cells displayed higher velocities on hard substrates than on soft substrates, with even larger gains in speed seen on glass. Ovarian-cancer cells exhib-

ited lower velocities, but were still most motile on soft substrates. The authors note that this phenomenon was mitigated in less metastatic cell lines, suggesting that it may be a property of metastatic cells.

Microarray analysisTo isolate the molecules responsible for these opposing responses, the researchers used microarray analy-sis to assess the expression of genes associated with the actomyosin cytoskeleton (the protein responsi-ble for regulating cytoskeletal ten-sion). They found that breast-cancer cells expressed higher levels of genes associated with actomyosin contrac-tion, such as myosin light chain, myo-sin heavy chain, myosin light chain kinase (MLCK) and RhoA. Ovarian-

cancer cells, meanwhile, expressed higher levels of genes associated with actin filament stabilization.

The researchers hypothesized that these different gene expressions could be responsible for the cell lines’ different responses to matrix rigid-ity, and investigated whether chemi-cally blocking these molecules could mitigate this behaviour.

To do this, they treated the cells to inhibit either Rho kinase (ROCK, which is activated by RhoA to increase cy toskeletal tension) , MLCK or non-muscle myosin II activity. Inhibiting ROCK or MLCK produced r igidity-independent behaviour in both cell lines. Inhibi-tion of non-muscle myosin in breast-cancer cells increased spreading on soft substrates and decreased spread on hard substrates.

They also tested whether increas-ing contractility in ovarian-cancer cells – to mimic the more contractile breast-cancer cells – could recover function on hard substrates. They found that this treatment increased the spread area and cell motility on hard substrates, but that, just like breast cancer, the ovarian-cancer cells with increased contractility now collapsed on soft substrates.

To investigate how the cells inter-act with their underlying substrates, the team performed traction-force cytometry. Both breast- and ovar-ian-cancer cells exerted two to three times more force on their preferred substrates (hard and soft, respec-tively). ROCK inhibition eliminated this force increase in both cell lines, but had no effect on forces exerted on less preferred substrates.

Inhibiting MLCK increased force exertion by breast-cancer cells on

both substrates, whereas in ovar-ian-cancer cells, it decreased force on the preferred soft substrate but did not affect cells on a hard sub-strate. Increasing contractility in ovarian-cancer cells with LPA increased force exertion on hard substrates but decreased force on soft substrates.

To investigate these disparities, the researchers analysed the spa-tial polarization (the force distri-bution relative to the cell centre) of the exerted forces. They found that while the total amount of force exerted by each cell did not correlate with cell motility, the polarization of these forces did.

Personalizing therapy“These studies can tell us a lot about bad ways to target metastasis, as well as new potential targets,” explained first author Daniel McGrail. “For instance, researchers have previ-ously shown that inhibiting ROCK does indeed block breast-cancer bone metastasis; however, it may also unintentionally increase lung metastasis by reducing cell contrac-tility enough to allow for the cells to survive in this softer tissue.”

Dawson added that the team hopes to apply its cell-behaviour findings to patient biopsies, to enable a person-alized approach to cancer treatment. “However, this study required the generation of more than 1000 indi-vidual substrates by hand – some-thing far from scalable to the clinic,” she said. “To address this, we are developing a high-content method to multiplex several of the experi-ments and automate the down-stream analysis to enable large-scale translation.”

The smallest category of particu-late air pollution, ultrafine particles (UFP) have a diameter less than 100 nm, penetrate the deepest into the lungs and take the longest to clear. An association between environ-mental particle concentrations and airway inflammation in adults and the worsening of symptoms in asth-matic children has previously been demonstrated. However, UFP levels vary between individuals, depend-ing on several factors including age and breathing rate.

Now, in the first measurements in individuals, an Israeli study has measured UFP in the airways of chil-dren with suspected asthma, and found them to correlate with spu-tum-detected inflammation and res-piratory symptoms. The researchers used an emerging non-invasive technique to detect UFP in exhaled breath condensate (EBC) that, based on their preliminary findings, has

the potential to improve the diagno-sis and monitoring of children with asthma ( J. Breath Res. 9 026001).

Currently, clinical practice relies heavily on spirometry measure-ments of lung function, but increas-ingly, data in the literature support the hypothesis that airway inflam-mation precedes deterioration in function in asthmatics. “Spirometry is far away from being sensitive in predicting exacerbation,” said senior author Elizabeth Fireman of the Tel Aviv Sourasky Medical Center and

Tel Aviv University.Conventional clinical techniques

for particle detection–bronchos-copy and bronchoalveolar lavage–are invasive, motivating Fireman and her colleagues to use non-inva-sive EBC testing instead. Using the technique, the patient exhales into a mouthpiece and their breath is con-densed in a cooled tube.

To count the UFP, the researchers used nanoparticle tracking analysis, where the breath condensate is illu-minated with a laser and particle size is determined by measuring the rate of Brownian motion. They used the technique in 52 children with respir-atory symptoms, including cough, wheezing and dyspnoea (shortness of breath), who had been referred for diagnostic assessment.

Each child’s symptoms, includ-ing wheezing and dyspnoea, were also rated and combined to give an overall breath score. Lung function was measured using spirometry. Depending on the tests requested by each referring doctor and each indi-vidual’s ability to complete the test,

some of the cohort also underwent routine bronchial provocation and fractional exhaled nitric oxide test-ing (FeNO), a breath test of airway inflammation.

Clinical feasibilityIn a second inflammation test, 17 out of the 52 also successfully completed induced sputum (IS) testing, where each inhaled saline solution via a nebuliser and then expectorated into a container. Using Giemsa staining, the proportion of cells in the sample that were eosinophils, a type of white blood cell and inflammation marker, was measured. Samples greater than 2.7% were classed as eosinophilic.

Thirty seven of the 52 individuals were diagnosed with asthma when they met one of four test criteria, which included reduced lung func-tion measured by spirometry and an eosinophilic IS test result. The remaining 15 individuals provided a control for comparison.

The EBC tests were easy to imple-ment and the researchers success-fully collected samples from all 52

children. They revealed that UFP levels measured using EBC were not significantly higher in children diag-nosed as asthmatic.

However, a univariate analy-sis did reveal significant correla-tions between both UFP counts and the percentage of particles that were UFP with individuals’ over-all breath symptom score and the incidence of wheezing. Further cor-relations between UFP levels and sputum eosinophilia were also dem-onstrated, but not with FeNO breath test results.

Based on the correlations, Fire-man is optimistic that both EBC and IS measurements have clinical value. “Biological monitoring with induced sputum and with exhaled breath condensate should be included in the routine screening of asthmatic chil-dren, together with the conventional work up done by spirometry.” How-ever, Fireman stressed that further studies are needed, including meas-urements on a larger cohort and an assessment of the reproducibility of the UFP measurements.

Research team: lead author Michelle Dawson (front, second from right), first author Daniel McGrail (front, centre) and other lab members.

Breath collection: a child with asthma undergoes a non-invasive external breath condensate test.

Particle pollutants detected in breath

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10 biomedicine

Gold nanotubes sizzle cancer cellsGold nanotubes could be used to photothermally destroy cancer cells, according to new research from the University of Leeds in the UK. The tubes, which are gold nanoparticles with tubular structures, could also be used as drug delivery vehicles and as nanoprobes for high-resolution imaging (Advanced Functional Materi-als 25 2117).

All living cells, including cancer cells, can be destroyed by heating them up. While some cancer cells may be resistant to chemotherapy, all cells can be denatured by heat – providing the temperature is high enough. Indeed, radiofrequency ablation and high-intensity focused ultrasound is routinely employed to thermally ablate tumours. Now, a team of researchers, led by Steve Evans of the School of Physics and Astronomy at Leeds, has found that gold nanotubes irradiated with near-infrared (NIR) light can also be used to photothermally destroy cancer cells.

Evans and colleagues say that they have succeeded in controlling the lengths of the nanotubes and were thus able to produce nanostruc-tures with just the right dimensions to optimally absorb light in the NIR

part of the electromagnetic spec-trum. The light absorbed by the tubes heats them up, and by using a single-wavelength pulsed laser beam, the researchers were able to rapidly increase the temperature in the vicinity of the tubes so that it was high enough to destroy cancer cells.

And that is not all: by adjusting the brightness of the laser pulse, Evans and colleagues say that they could use the nanotubes to either destroy cancer cells or to image tumours.

For the imaging part, they made

use of a new type of technique called multispectral optoacoustic tomography (MSOT), in which they detected the ultrasound waves pro-duced by the gold nanotubes in colo-rectal cancer cells in mice. In their experiments, the researchers intra-venously injected the nanotubes into the animals and observed that the nanomaterials accumulated at the tumour sites.

Since the nanotubes have a hol-low central core, they can be loaded with anticancer drugs too, says

team member James McLaughlan from the School of Electronic and Electrical Engineering. “Combining targeting and localised release of therapeutic agents in this way could be used to identify and treat cancer with minimal toxicity to the patient.” Indeed, the researchers say that the mice excreted the gold nanotubes in around 72 hours, so they are there-fore unlikely to be toxic to living organisms – an important point to consider when developing nanopar-ticles for biomedical applications. The fact that the tubes are coated with poly(sodium 4 -styrenesul-fonate) (PSS) also makes them less toxic to healthy cells while they are in the bloodstream.

Younan Xia of Georgia Tech in the US, who was not involved in this work, commented: “although other types of gold structures, including nanocages, nanorods and nanoshells have been used to destroy tumours before now, the new aspect in this work is the potential improvement in terms of tumour targeting efficacy by altering the shape or morphology of the nanostructures.”

Belle Dumé is contributing editor at nanotechweb.org.

Radiotherapy is a powerful treat-ment for brain cancer, but can also cause injury to the brain. Researchers at Memorial Sloan Kettering Cancer Center have developed a way to use stem cells to repair such damage. During irradiation, oligodendrocyte progenitor cells – which are criti-cal for shielding and repairing the brain’s neurons throughout life - are lost or significantly depleted. The team investigated whether stem cells could be coaxed to replace these lost oligodendrocytes, and saw that this could be achieved by growing human embryonic stem cells, or induced pluripotent stem cells, in the pres-ence of certain growth factors and other molecules (Cell Stem Cell 16 198).

The researchers then used the lab-grown cells to treat irradiated rats. When the cells were injected into the brain, brain repair was evident and rats regained the cognitive and motor skills lost due to radiation exposure. Importantly, none of the animals developed tumours or inappropriate cell types in the brain. “This will have to be proven further, but if we can repair the brain effectively, we could be bolder with our radiation dosing, within limits,” said team leader Vivi-ane Tabar.

Artist’s impression: pulsed NIR light (red) shines onto a tumour. The tumour is imaged by multispectral optoacoustic tomography via the ultrasound emission (blue) from the gold nanotubes.

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Physical OncologyNow open for submissionsConvergent Science™ Physical Oncology (CSPO) is the first interdisciplinary journal dedicated to integrating physical sciences with cancer biology and clinical oncology to advance our understanding and treatment of cancer in patients.

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Tests of a system that combines the benefits of both PET and MRI have been successful, according to a group of researchers in Germany and the UK. The system is currently in the pre-clinical phase, but prom-ises to improve diagnosis by offering simultaneous insight into a subject’s anatomy and metabolic processes (Phys. Med. Biol. 60 2231).

PET is a technique for imaging metabolic processes in the body that requires a positron-emitting tracer to be introduced into the body. The emitted positrons interact with elec-trons in tissue, generating a pair of gamma rays that can be recorded on a detector – in turn revealing the exact position of the tracer.

PET is good at imaging metabolic processes, but not so good at imag-ing their context – namely the sur-rounding anatomy. For that reason, PET has been combined with other types of medical imaging, such as CT – which requires several X-ray scans to be combined into a three-dimensional image.

Unfortunately, the X-rays in CT scans are harmful in large quanti-ties. For that reason, researchers have tried to combine PET with MRI, which does not emit ionizing radiation and which has more varied modes of operation. Functional MRI, for instance, reveals brain activity by monitoring the flow of blood. But it is not easy to integrate PET with MRI. An MRI scanner is sensitive to the

presence of electronic devices, while a PET detector can be disrupted by the strong magnetic fields employed in an MRI bore. According to medi-cal physicists Jakob Wehner and Volkmar Schulz at RWTH Aachen University, that has led previous sys-tems to suffer some compatibility issues.

Compatible approachNow Schulz’s group has tested a new PET system that promises much bet-ter compatibility. Known as Hyper-ion-IID, the detector relies on a digital silicon photomultiplier to capture the tracer’s gamma rays. The digital silicon photomultiplier is a fairly new invention that does not require the transmission of an analogue signal through an MRI bore, and is therefore less subject to noise from the magnetic field. The researchers tested the device by assessing the performance of the MRI machine and the PET system in turn.

They found an “acceptable” level of degradation of all the MRI machine’s subsystems: its static

magnetic field (for aligning pro-tons in tissue), its radio subsystem (for def lecting those protons and measuring their relaxation time, thereby defining the tissue type) and its gradient magnetic field (for performing more advanced MRI). For the PET system, they found only negligible degradation unless the MRI machine’s gradient magnetic field was employed. “When normal imaging sequences are applied, the level of degradation is negligible,” says Wehner. “This means that nor-mal simultaneous PET/MRI applica-tions are not harmed.”

The results show that the Hype-rion-IID system is “definitely” a success, add Wehner and Schulz. “The level of MR-compatibility is, in comparison to other combined systems, on a very good level,” says Schulz. “The system is performing stably, meaning that pre-clinical in vivo studies – mouse imaging experi-ments – are absolutely possible. In fact, the first in vivo tests have already been performed and the results will be published soon.”

SPECT delivers ultrahigh sensitivity

Researchers from the Netherlands recently described their ability to perform in vivo molecular radionu-clide imaging of small laboratory animals with quarter-millimetre resolution, using a new-generation SPECT/CT system. The team has now conducted additional studies that illustrate the possibility of per-forming dynamic SPECT with one second time frames, or static SPECT with fractions of a megabecquerel of activity ( J. Nucl. Med. 56 470).

The U-SPECT+ SPECT/CT system was developed by MILabs, a com-mercial spinoff from the University Medical Centre Utrecht. The system uses three 595 × 472 mm NaI(Tl) sta-tionary detectors, a set of replaceable focusing multi-pinhole collimators, and a user interface designed for both total-body SPECT and 3D-focused imaging.

For this study, the researchers used a cylindrical collimator designed to fit mouse-sized animals, with 54 focused 2.0 mm diameter conical pinholes. The centre of each pinhole was placed on the inner wall surface of the collimator tube, in order to minimize the object–pinhole dis-tance and maximize the pinhole–detector distance. This design both improved sensitivity and, by increas-ing the magnification factor, resolu-tion characteristics.

Lead author Oleksandra Ivash-chenko of the Reactor Institute Delft and co-authors evaluated the perfor-mance of the new collimator using phantoms. They also performed static and rapid dynamic ultralow-dose imaging in live mice.

The reseachers measured the sensitivity of the collimator along the axial and transaxial directions in counts per second per megabec-querel of activity (cps/MBq), by scanning a 99mTc point source of known activity through the centre of the field-of-view (FOV). They per-formed dynamic 30 min acquisitions using 5 min frames.

Rods could be distinguished with diameters down to 1.1 mm using 0.25 MBq, and down to 0.85 mm using 5 MBq. The minimal visible rod diameter for the 0.25 MBq activ-ity scan improved to 0.95 mm within the 30 minutes of acquisition time.

The peak sensitivity of the collima-tor reached 1.3% for 99mTc.

“The resolution phantom scans illustrated that the collimator can maintain a sub-millimetre resolu-tion (0.95 mm) with 0.25 MBq when a 30 min acquisition is used,” the authors wrote. “Such performance makes the collimator most suitable for either sub-megabecquerel static scans or several-megabecquerel fast dynamic scans.”

The team next performed low-dose bone SPECT scans, fast dynamic cardiac scans and microdose renal function SPECT scans using anaes-thetized C57BL/6 mice. All SPECT scans were acquired for 30 min with the ultrahigh-sensitivity collima-tor. Top- and side-view maximum-intensity projections of the total body scan illustrated that a 3.5 MBq scan provided details of the ana-tomic structures in the mouse skel-eton, such as in the pelvis, skull, and both upper and lower limbs.

The researchers were able to reach a time frame of as low as 15 s with a sub-megabecquerel level of activity. They explained that this capability allows analysis of tracer dynamics from both time–activity curves and from the dynamic sequence of SPECT images. Also, the bio-distribution of the radiolabelled compound within an organ or system of organs can be illustrated. Another benefit is that scans can be repeated because the low level of required activity would prevent a harmful radiation dose from accumulating in the animal.

Based on their research, the authors recommend use of the ultrahigh-resolution collimator: to improve the frame rate for dynamic biokinetic screening during the development of new tracers or imag-ing of biologic processes with fast dynamics; to increase the number of applications for imaging of organs with low specific uptake, or for trac-ers and nanocarriers that have low labelling efficiency; and to reduce the dose to a laboratory animal dur-ing follow-up molecular imaging studies.

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

Sub-megabecquerel scanning: the U-SPECT+/CT system from MILabs.

Hyperion-IID: (left) the PET insert mounted on a clinical 3T MRI scanner; (right) dedicated Tx/Rx MRI coil designed for the PET/MRI insert.

PET insert relies on digital SiPMs

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Nanocomposites encourage bone repairArtificial bone implants could pro-vide a means of avoiding the pain and limitations of using the patient’s own bone in fracture treatments. Now, researchers in India demon-strate that graphene-oxide nano-flakes can enhance the properties of artificial hydroxyapatite composites to provide supportive scaffolds that encourage bone repair (Nanotechnol-ogy 26 161001).

“The greatest challenge is to design a biomaterial that should match the properties of native healthy bone,” said Manitha Nair, who produced these latest results alongside col-leagues at the Amrita Institute of the Medical Sciences and Research Cen-tre in India. “Properties like biocom-patibility, chemical composition, porosity, degradation and mechani-cal stability are very critical to decide the success of the biomaterial.”

Traditionally, bone fractures that fail to heal spontaneously are treated with bone grafts, where the dam-aged area is replaced with healthy bone harvested from elsewhere in the body. However, this can cause damage to the area where the bone is harvested, as well as significant discomfort to the patient. There are also limits to how much bone mate-rial can be obtained this way.

Natural bone is formed from hydroxyapatite – a porous phospho-rous and calcium structure – and collagen. However, the expense of obtaining collagen inhibits direct replication of these structures,

prompting investigations to deter-mine whether gelatin – a denatured weaker collagen-like material – might be a suitable substitute.

Graphene is renowned for its mechanical strength, among many other material attributes. In their latest work, Nair and her colleagues studied how graphene-oxide nano-f lakes in bone scaffolds might enhance hydroxyapatite/gelatin

nanocomposite bone implants.When a fracture mends, stem cells

differentiate into osteoblast cells and mend the break. However the stem cells need to migrate from the sur-rounding area to the damaged site, which can take time, particularly in the elderly who have lower numbers of stem cells.

“It has been suggested that includ-ing stem cells into the compos-

ite scaffold and implanting them together would alleviate the need to wait for cell migration,” said Nair. However, she goes on to describe the delays accrued with this approach because stem cells need to be isolated from the patient and then multiplied in culture before the implant, all of which can take a few weeks.

While pristine graphene is prone to agglomerating, graphene oxide has chemical characteristics that can be positively beneficial to cell health while retaining graphene’s mechani-cal advantages. The team cultured mesenchymal cells – which can dif-ferentiate into various types of tissue – and monitored the differentiation of these cells into bone.

They found that graphene-oxide nanof lakes greatly expedited the multiplication of stem cells and seemed to encourage differentiation into bone tissue cells. “Even with just the basic culture medium, graphene oxide induces differentiation of stem cells into osteoblasts,” said Nair.

While the team’s preliminary tests have been promising, further work is needed to check the toxicity of gra-phene-oxide-enhanced hydroxyapa-tite/gelatin structures.

Next, Nair and colleagues plan to implant the graphene-oxide-enhanced scaffolds in live animals to test the toxicity, as well as the speed and quality of bone regeneration.

Anna Demming is online editor of nanotechweb.org.

Earlier this year, David Williams became the first human to have a new radiation treatment implanted in the centre of his brain tumour. The tech-nology, developed at the UT Health Science Center, uses a thin catheter to insert 100 nm-diameter, highly-radioactive liposomes directly into the tumour. At his first follow-up appointment, Williams said that he did not experience the side-effects normally associated with conven-tional radiotherapy, which also irradiates healthy tissue. “The tech-nology is unique,” said neuro-oncol-ogist Andrew Brenner. “Only we can load the liposomes to these very high radioactivity levels.”

One challenge of this approach is getting the nano-liposomes into the brain. To do this, the team designed an improved catheter that can deliver small quantities to precise locations. “The main limitation right now is we have to start with small-sized tumours, until we get a better handle on our delivery methods, to make sure we can cover larger tumours,” Brenner said.

Promoting cell growth: mesenchymal cells on composite scaffolds after 24 h. Confocal micrographs showing viable cells in green (top panel); scanning electron micrographs showing cell morphology (lower panel).

Trial leader: Andrew Brenner.

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14 medical imaging

A diffusion-based MRI technique has demonstrated superior sensitivity to conventional imaging approaches in detecting the spread of prostate cancer in an in vivo feasibility study. Developed by researchers in the US, restriction spectrum imaging (RSI)-MRI detects diseased tissue by selectively imaging the intra-cellular diffusion of water in malignant and healthy cells, and corrects for image distortions due to magnetic field inhomogeneities (Prostate Cancer Pro-static Dis. 18 81).

“This new approach is a more reli-able imaging technique for localiz-ing tumours,” said first author and physician scientist Rebecca Rakow-Penner of the University of Califor-nia San Diego (UCSD). “It provides a better target for biopsies, especially for smaller tumours.” Other poten-tial applications include surgical planning and disease staging and surveillance.

Not all tumours are detect-able using the standard technique, contrast-enhanced MRI. A second approach, diffusion-weighted MRI, is more sensitive, detecting malig-nant tissue by the reduced mobility of water molecules within it. How-ever, false positives can be produced by inflammation and haemorrhage following a biopsy, and ongoing research by the UCSD group has revealed that distortions due to magnetic field inhomogeneities can misplace the tumour by up to 1.2 cm.

Developed by UCSD researchers led by senior author Anders Dale, RSI-MRI has already demonstrated improved detection and delineation of brain tumours. The improvements stem from an imaging sequence that is tuned to detect the isotropic dif-fusion of water inside a cell, rather than in the extra-cellular space that conventional diffusion MRI detects.

Cell size mattersThe technique detects diffusion over a “spectrum” of distances, including distances at the cellular level. The mechanism by which it detects can-cer cells is still under investigation by the researchers. However, they hypothesize that it relates to the size of cell nuclei relative to the cell volume. Cells with a relatively large nucleus – that are more likely to be malignant – are thought to contrib-ute more to the intra-cellular diffu-sion signal than cells with a small nucleus that tend to be benign. The RSI-MRI technique also corrects geometric distortions in the images

with an alternating phase-encode technique developed at UCSD.

The researchers scanned 28 patients, acquiring RSI-MRI images in addition to conventional T2 and diffusion-weighted images on a 3T scanner using an endorectal coil. Each patient had been diagnosed with prostate cancer by biopsy and underwent radical prostatectomies following the scans.

Histological analysis of the excised tissue revealed that 10 of the 28 had extraprostatic disease spread. After excluding one patient (due to an error in data collection), a panel of radiolo-gists, urologists and uropathologists looked, non-blinded, for evidence of extraprostatic disease in the remain-ing images.

Examining RS images alone, the panel found evidence of disease extension in eight out of the nine patients. In contrast, the conven-tional images were consistent with extension in only two individuals, while a third case was classed as suspicious.

Based on their findings to date, Rakow-Penner expects RSI-MRI to have a “significant” impact on patient care. The modality is already in clinical use at UCSD. “RSI-MRI results are now part of our radiol-ogy reporting and can be viewed by the referring surgeon or radiation oncologist.”

In ongoing research, the authors are undertaking a blinded study to further evaluate the technique’s abil-ity to detect extraprostatic disease and a separate investigation of its efficacy in ultrasound-MRI fusion guided biopsies.

Multi-detector CT (MDCT) is the frontline imaging modality for diag-nosing acute traumatic brain injury (TBI), using non-contrast-enhanced scans to detect fresh blood in the brain. The ability to accurately diag-nose TBI at the earliest stage, such as in the ambulance or even at the location where the injury occurred, would be of great help in deter-mining the appropriate treatment course. However, MDCT is unsuit-able for point-of-care approaches due to its high cost, large footprint and lack of portability.

Flat-panel detector (FPD)-based cone-beam CT (CBCT) could be far more suitable for point-of-care imag-ing. However, existing FPD-CBCT systems usually offer poor contrast and increased artefacts when imag-ing soft tissues or blood. To tackle these limitations, a team from Johns Hopkins University has developed an artefact correction framework for processing FPD-CBCT brain images (Phys. Med. Biol. 60 1415).

“Cone-beam CT with an FPD can capture a full volumetric image in a single or half rotation, permitting a relatively simple gantry structure that does not require translation of the patient to acquire a full 3D image,” explained senior author Jef-frey Siewerdsen. “This facilitates a simpler, smaller scanner that could be well suited to point-of-care imag-ing. This would allow us to get the scanner to the patient, rather than bringing the patient to the scanner, which can cost valuable time.”

Diagnosing acute TBI requires detection of bleeds that range from over 10 mm in size for severe TBI to millimetre-sized haemorrhages associated with mild-to-moderate TBI and diffuse axonal injury. “One of the main factors limiting the high level of image quality required for intracranial imaging is X-ray scat-ter,” explained first author Alejandro Sisniega. “For this reason, we have implemented a high-speed Monte Carlo [MC] method for scatter cor-rection.” Other obstacles in creating high-quality CBCT images include detector lag, veiling glare and beam hardening.

The researchers developed a computational framework that addresses all four of these chal-lenges. The principal component is a novel MC-based scatter correction technique that combines graphic processing unit (GPU) acceleration, variance reduction and sparse MC simulations to yield a runtime of about 4 min per scan.

Performance testsThe Hopkins team quantified the performance of the correction framework using a head phantom containing a gelatin mixture to sim-ulate the brain and acrylic spheres as surrogates for blood. This provided a blood-to-brain contrast of 50 HU, appropriate to the 15–55 HU seen in brain haemorrhages.

Using a bench-top FPD-CBCT set-up, the researchers compared images computed with and without each correction component, to quantita-tively evaluate (in HU) improvement in image uniformity and reduction of artefacts. Reconstructions before lag correction showed a “comet” artefact that was reduced by about 16 HU after correction.

Data reconstructed with scatter correction showed a reduction in cupping and streak artefacts, as well as improved image uniformity. One iteration of scatter plus beam harden-ing correction significantly reduced artefacts. After four iterations (14 min runtime), image uniformity approached that of the narrow-beam reconstruction and streak artefacts were almost completely suppressed.

Finally, the researchers used the entire artefact correction framework to process FPD-CBCT images of the head phantom. Uncorrected images were of non-diagnostic quality. After correction, image non-uniformity was reduced to around 20% of its original value and artefacts reduced to a level that enabled visualization of 3 mm bleeds.

The researchers are now working to create a dedicated point-of-care CBCT scanner. “A prototype scan-ner based on this work is underway, with first clinical studies to follow,” said Siewerdsen.

Artefact correction framework: (top row) uncorrected CBCT images of a head phantom with simulated intracranial haemorrhage; (middle row) images after artefact correction; (bottom row) difference images.

Improving diagnosis: restriction spectrum imaging of a patient with high-grade prostate cancer.

CBCT eyes point-of-care imagingRSI-MRI detects prostate cancer

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