The ALICE Collaboration has measured with improved precision the production of J/ψ mesons in collisions of lead nuclei at the highest LHC energy, confirming the role of the “regeneration mechanism” in J/ψ production.
J/ψ mesons are bound states of a charm (c) and anticharm (c) quark and they are particularly sensitive probes of the quark–gluon plasma (QGP) formed in high-energy heavy-ion collisions. The production of J/ψ mesons is suppressed in the QGP by the screening of the cc binding, which is generated by the large surrounding colour-charge density. Such suppression was observed at RHIC in the US in AuAu collisions at a collision energy of 0.2 TeV and at the CERN SPS in PbPb collisions at 17.6 GeV. Using data from LHC Run 1, ALICE also measured a suppression in PbPb collisions at 2.76 TeV. However, the value was smaller than that measured at lower collision energy (see CERN Courier March 2012 p14), which was found to be consistent with a new mechanism of J/ψ production in the QGP: regeneration by recombination of deconfined charm and anticharm quarks.
The J/ψ suppression is quantified by the nuclear modification factor (RAA), which is defined as the ratio of the yield in PbPb to that in an equivalent number of pp collisions. The J/ψ RAA measured by ALICE as a function of the average number of nucleons participating in the collision in PbPb collisions at 5.02 TeV is compared to the value at 2.76 TeV. The larger the number of participating nucleons, the more head-on and violent the collisions.
A clear decreasing trend of the RAA with increasing participating nucleons is observed for peripheral collisions, followed by a constant evolution for more central collisions (see figure). Thanks to the increased integrated luminosity delivered by the LHC, the higher collision energy and improved detection techniques, the accuracy of the new measurement is highly improved and confirms ALICE’s earlier observation. In short, at LHC energies, a J/ψ regeneration mechanism competes with the J/ψ suppression mechanism, both of which are due to the formation of the QGP.
The improved accuracy of the RAA measurement at 5.02 TeV imposes strong constraints on theoretical calculations, the uncertainties of which are now significantly larger than the experimental ones. The additional data expected to be accumulated during LHC Run 2 will further constrain the models through more differential measurements, including the J/ψ elliptic flow.
The bumper data harvest at LHC Run 2 continues for the LHCb experiment. In mid-August, the collaboration celebrated the milestone of 1 fb–1 integrated luminosity collected so far during 2016, with significantly more expected to come during the remainder of the year. This corresponds to the production of around 1012 beauty hadrons, of which the most interesting decays have been selected and recorded for offline analysis. The stupendous performance of the LHC has been central to this success. Indeed, the LHCb operations team has had to adjust trigger and offline procedures to prevent the torrent of incoming data from overflowing the experiment’s data-storage resources.
The ratio of differential cross-sections for b-hadron production with respect to pseudorapidity, η, measured at collision energies of 13 and 7 TeV. Data are compared to predictions described in Eur. Phys. JC 75 610.
With LHCb’s physics programme centred around painstaking precision measurements, the most eagerly awaited results from the Run 2 data set will not begin to appear until early next year. However, the first glimpses into the new sample are already revealing surprising results. For example, a measurement of the production cross-section of beauty hadrons at 13 TeV has shown unexpected behaviour when compared to what was observed at 7 TeV during Run 1. Although the ratio of the cross-sections at the two energies is roughly equal to two, as predicted, there is a clear dependence on pseudorapidity (which is related to the angle of production) that differs markedly from the current model expectations. The ratio in the data is significantly higher at low values of pseudorapidity, which corresponds to the more central regions of production (see figure).
This result, which was first shown at the ICHEP conference in Chicago in August, is still being digested by theorists. Although it is too early to speculate on the causes of this intriguing behaviour, and indeed the consequences for other measurements, it is hoped that many other surprises lurk in the Run-2 data set.
Understanding the nature of dark matter (DM) is the focus of extensive research at collider- and astrophysics-based experiments. The most well-known signature for DM production at the LHC is the so-called “mono-X” topology, for which events are characterised by the presence of a high-momentum object (e.g. a jet in the case of a mono-jet signature) from initial-state radiation in combination with significant missing transverse energy (ETmiss). The ETmiss signature may arise from DM particles that are stable yet electrically neutral and part of a colour-singlet, which means they will escape detection in the CMS experiment.
For a large class of DM models, however, the mediator cannot only be probed by conventional DM searches (such as the mono-X plus ETmiss analyses) but also by direct searches for the mediator. Such searches measure the mediator’s decay into Standard Model (SM) particles such as quarks, gluons and leptons. The most prominent example is the dijet-resonance search but also, depending on specific properties of the DM model considered, dilepton and diphoton searches may be relevant.
Using proton–proton collision data from the LHC collected at a centre-of-mass energy of 13 TeV, the CMS collaboration has recently updated several of its DM searches and placed stringent constraints on interesting DM parameter space (see figure 1). The limits shown in this plot are obtained by interpreting different collider searches from CMS in a simplified DM model. The model corresponds to an axial-vector mediator particle that is excited in proton–proton collisions and decays into two DM particles (figure 2, right) or SM particles (figure 2, left).
Although the absolute exclusions provided by these searches depend strongly on the chosen coupling and DM model scenario, the example of the axial-vector model illustrates that, in addition to the conventional mono-X plus ETmiss searches, dijet constraints can place significant bounds on relevant DM models and thus are an important ingredient in our quest of searching for DM at colliders.
Astronomers have found clear evidence of a planet orbiting the closest star to Earth, Proxima Centauri. The extrasolar planet is only slightly more massive than the Earth and orbits its star within the habitable zone, where the temperature would allow liquid water on its surface. The discovery represents a new milestone in the search for exoplanets that possibly harbour life.
Since the discovery of the first exoplanet in 1995, more than 3000 have been found. Most were detected either via radial velocity or transit techniques. The former relies on spectroscopic measurements of the weak back-and-forth wobbling of the star induced by the gravitational pull of the orbiting planet, while the latter method measures the slight drop in the star’s brightness due to the occultation of part of its surface when the planet passes in front of it.
Exoplanets discovered so far exhibit a diverse range of properties, with masses ranging from Earth-like values to several times the mass of Jupiter. Massive planets close to their parent star are the easiest to find: the first known exoplanet, called 51 Peg b, was a gaseous Jupiter-sized planet (a “hot Jupiter”) with a temperature of the order of 1000 °C due to its proximity to the star. The ultimate goal of exoplanet hunters is to find an Earth twin or at least an Earth-sized planet at the right distance from its parent star to have liquid water on its surface. This condition defines the habitable zone, which is the range of distance around the star that would be suitable for life.
Proxima Centauri b orbits the star (Proxima Centauri) in only 11.2 days and has a minimum mass of 1.27 Earth masses.
Proxima Centauri b matches this condition and is also a special planet for us because it orbits our nearest star, located just 4.2 light-years away. Near does not necessarily mean bright, however. Proxima Centauri is actually a cool red star that is much too dim to be seen with the naked eye and, with a mass about eight times smaller than the Sun, it is also around 600 times less luminous. The habitable zone around this red-dwarf star is therefore at much shorter distances than the corresponding distances in our solar system – equivalent to a small fraction of the orbit of Mercury. Proxima Centauri b orbits the star in only 11.2 days and has a minimum mass of 1.27 Earth masses. The exact value of the mass cannot be determined by the radial-velocity method because it depends on the unknown inclination of the orbit with respect to the line of sight.
During the first half of 2016, Proxima Centauri was regularly observed with the HARPS spectrograph on the ESO 3.6 m telescope at La Silla in Chile, and simultaneously monitored by other telescopes around the world. This campaign, which was led by Guillem Anglada-Escudé of Queen Mary University of London and shared publicly online as it happened, was called the Pale Red Dot.
The final results have now been published, concluding with a discussion on the habitability of the planet. Whether there is an atmosphere and liquid water on the surface is the subject of intense debate because red-dwarf stars can display quite violent behaviour. The main threats identified in the paper are tidal locking (for example, does the planetalways present the same face to the star, as does our Moon?), strong stellar magnetic fields and strong flares with high ultraviolet and X-ray fluxes. Whereas robotic exploration is some time away, the future European Extremely Large Telescope (E-ELT) should be able to see the planet and probe its atmosphere spectroscopically.
This summer, the city of Chicago in Illinois was not only a vacation destination for North American tourists – it was also the preferred destination for more than 1400 scientists, students, educators and members of industry from around the world. Fifty-one countries from Africa, Asia, Australia, Europe, North America and South America were represented at the 38th International Conference on High Energy Physics (ICHEP), which is the largest such conference ever held.
Indeed, the unexpectedly large interest in the meeting caused some re-thinking of the conference agenda. A record 1600 abstracts were submitted, of which 600 were selected for parallel presentations and 500 for posters by 65 conveners. During three days of plenary sessions, 36 speakers from around the world overviewed results presented at the parallel and poster sessions.
One of the most popular parallel-session themes concerned enabling technologies, totalling around 400 abstract submissions, and rich collaborative opportunities were discussed in the new “technology applications and industrial opportunities” track. Another innovation at ICHEP 2016 concerned diversity and inclusion, which appeared as a separate parallel track. A number of new initiatives in communication, education and outreach were also piloted. These included lunchtime sessions aimed at increasing ICHEP participants’ skills in outreach and communication through news and social media, “art interventions” and a physics slam, where five scientists competed to earn audience applause through presentations of their research. The outreach programme was complemented by events at 30 public libraries in Chicago and a public lecture about gravitational waves.
While the public had an increasing number of ways to connect with the conference, however, the main attraction for attendees remained the same: new science results. And no result was more highly anticipated than the updates on the 750 GeV diphoton resonance hinted at in data from the ATLAS and CMS experiments recorded during 2015.
Exploring the unknown
The spectacular performance of the LHC during 2016, which saw about 20 fb–1 of 13 TeV proton–proton collisions delivered to ATLAS and CMS by the time of the conference, gave both experiments unprecedented sensitivity to new particles and interactions. The collaborations reported on dozens of different searches for new phenomena. In a dramatic parallel session, both ATLAS and CMS revealed that their 2016 data do not confirm the previous hints of a diphoton resonance at 750 GeV (figure 1); apparently, those hints were nothing more than tantalising statistical fluctuations. Disappointed theorists were happily distracted by other new results, however. As expected, these include interesting excesses worth keeping an eye on as more data become available. Still in the running for future big discoveries are the production of heavy particles predicted by supersymmetry and exotic theories, and the direct production at the LHC of dark-matter particles. So far, no signs of such particles have been seen at ATLAS or CMS.
Many other experiments reported on their own searches for new particles and interactions, including new LHCb results on the most sensitive search to date for CP violation in the decays of neutral D mesons which, if detected, would allow researchers to probe CP violation in the up-type quark sector. Final results from the MEG (Mu to E Gamma) experiment at the Paul Scherrer Institute in Switzerland revealed the most sensitive search to date for charged lepton-flavour violation, which would also be a clear signature of new physics. Using bottom and charm quarks to probe new physics, the Beijing Spectrometer (BES) at IHEP in China and the Belle experiment at KEK in Japan showcased a series of precision and rare-process results. While they have a few interesting discrepancies from Standard Model (SM) predictions, presently no signs of physics beyond the SM have emerged.
Meanwhile on the heavy-ion front, the ALICE experiment at the LHC joined ATLAS, CMS and LHCb in presenting new observations of the dramatic and mysterious properties of quark–gluon plasma. This was complemented by results from the STAR and PHENIX experiments at RHIC at the Brookhaven National Laboratory in the US.
Rediscovering the Higgs
Perhaps unsurprisingly, given that its discovery in 2012 was one of the biggest in particle physics for a generation, the Higgs boson was the subject of 30 parallel-session talks. New LHC measurements are a great indicator of how the Higgs boson is being used as a new tool for discovery. Already Run 2 of the LHC has produced more Higgs bosons than in Run 1, and the Higgs has been “rediscovered” in the new data with a significance of 10σ (figure 2). A major focus of the new analyses is to demonstrate the production of Higgs particles in association with a W or Z boson, or with a pair of top quarks and their decay patterns. These production and decay channels are important tests of Higgs properties, and so far the Higgs seems to behave just as the SM predicts.
About 20 new searches looking for heavier cousins of the Higgs were reported. These “heavy Higgs”, once produced, could decay in ways very similar to the Higgs itself, or might decay into a pair of Higgs bosons. Other searches covered the possibility that the Higgs boson itself has exotic decays: “invisible” decays into undetected particles, decays into exotic bosons or decays that violate the conservation of lepton flavour. No signals have emerged yet, but the LHC experiments are providing increasing sensitivity and coverage of the full menu of possibilities.
Neutrino mysteries
With neutrinos currently among the most interesting objects to study to look for signs of physics beyond the SM, ICHEP included reports from three powerful long-baseline neutrino experiments: T2K at J-PARC in Japan, and NOνA and MINOS at Fermilab in the US, which are addressing some of the fundamental questions about neutrinos such as CP violation, the ordering of their masses and their mixing behaviour. While not yet conclusive, the results presented at ICHEP show that neutrino physics is entering a new era of sensitivity and maturity. Data from T2K currently favour the idea of CP violation in the lepton sector, which is one of the conditions required for the observed dominance of matter over antimatter in the universe, while data from NOνA disfavour the idea that mixing of the second and third neutrino flavours is maximal, representing a test of a new symmetry that underlies maximal mixing (figure 3).
With nearly twice the antineutrino data in 2016 compared with its 2015 result, the T2K experiment’s observed electron antineutrino appearance rate is lower than would be expected if CP asymmetry is conserved (left). With data accumulated until May 2016, representing 16% of its planned total, NOvA’s results (right) show an intriguing preference for non-maximal mixing – that is, a preference for sin2θ23 ≠ 0.5.
The long simmering issue of sterile neutrinos – hypothesised particles that do not interact via SM forces – also received new attention in Chicago. The 20 year-old signal from the LSND experiment at Los Alamos National Laboratory in the US, which indicates 4σ evidence for such a particle, was matched some years ago by anomalies from the MiniBooNE experiment at Fermilab. As reported at ICHEP, however, cosmological data and new results from IceCUBE in Antarctica and MINOS+ at Fermilab do not confirm the existence of sterile neutrinos. On the other hand, the Daya Bay experiment in China, Reno in South Korea and Double Chooz in France all confirm a reactor neutrino flux that is low compared with the latest modelling, which could arise from mixing with sterile neutrinos. However, all three of these experiments also confirm a “bump” in the neutrino spectrum at an energy of around 5 MeV that is not predicted, so there is certainly more work to be done in understanding the modelling.
Probing the dark sector
Dark matter dominates the universe, but its identity is still a mystery. Indeed, some theorists speculate about the existence of an entire “dark sector” made up of dark photons and multiple species of dark matter. Numerous approaches are being pursued to detect dark matter directly, and these are complemented by searches at the LHC, surveys of large-scale structure and attempts to observe high-energy particles from dark-matter annihilation or decay in or around our Galaxy. Regarding direct detection, experiments are advancing steadily in sensitivity: the latest examples reported at ICHEP came from LUX in the US and PandaX-II in China, and already they exclude a substantial fraction of the parameter space of supersymmetric dark-matter candidates (figure 4).
Dark energy – the name given to the entity thought to be driving the cosmic acceleration of today’s universe – is one of two provocative mysteries, the other concerning the primordial epoch of cosmic inflation. ICHEP sessions concerned both current and planned observations of such effects, using either optical surveys of large-scale structure or the cosmic microwave background. Both approaches together can probe the nature of dark energy by looking at the abundance of galaxy clusters as a function of redshift; as reported at the Chicago event, this is already happening via the Dark Energy Survey and the South Pole Telescope.
Progress in theory
Particle theory has been advancing rapidly along two main lines: new ideas and approaches for persistent mysteries such as dark matter and naturalness, and more precise calculations of SM processes that are relevant for ongoing experiments. As emphasised at ICHEP 2016, new ideas for the identity of dark matter have had implications for LHC searches and for attempts to observe astrophysical dark-matter annihilation, in addition to motivating a new experimental programme looking for dark photons. A balanced view of the naturalness problem, which concerns the extent to which fundamental parameters appear tuned for our existence, was presented at ICHEP. While supersymmetry is still the leading explanation, theorists are also studying alternatives such as the “relaxion”. This shifts attention to the dynamics of the early universe, with consequences that may be observable in future experiments.
There have also been tremendous developments in theoretical calculations with higher-order QCD and electroweak corrections, which are critical for understanding the SM backgrounds when searching for new physics – particularly at the LHC and, soon, at the SuperKEKB B factory in Japan. The LHC’s experimental precision on top-quark production is now reaching the point where theory requires next-to-next-to-next-to-leading-order corrections just to keep up, and this is starting to happen. In addition, recent lattice QCD calculations play a key role in extracting fundamental parameters such as the CKM mixing matrix, as well as squeezing down uncertainties to the point where effects of new phenomena may conclusively emerge.
Facilities focus
With particle physics being a global endeavour, the LHC at CERN serves as a shining example of a successful large international science project. At a session devoted to future facilities, leaders from major institutions presented the science case and current status of new projects that require international co-operation. These include the International Linear Collider (ILC) in Japan, the Circular Electron–Positron Collider (CEPC) in China, an energy upgrade of the LHC, the Compact Linear Collider (CLIC) and the Future Circular Collider (FCC) at CERN, the Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) in the US, and the Hyper-K neutrino experiment in Japan.
While the high-energy physics experiments of the future were a key focus, one of the well-attended sessions at ICHEP 2016 concerned professional issues critical to a successful future for the field of particle physics. Diversity and inclusion were the subject of four hours of parallel sessions, discussions and posters, with themes such as communication, inclusion and respect in international collaboration and how harassment and discrimination in scientific communities create barriers to access. The sessions were mostly standing-room only, with supportive but candid discussion of the deep divides, harassment, and biases – both explicit and implicit – that need to be overcome in the science community. Speakers described a number of positive initiatives, including the Early Career, Gender and Diversity office established by the LHCb collaboration, the Study Group on Diversity in the ATLAS collaboration, and the American Physical Society’s “Bridge Program” to increase the number of physics PhDs among students from under-represented backgrounds.
ICHEP 2016 clearly showed that there are a vast number of scientific opportunities on offer now and in the future with which to further explore the smallest and largest structures in the universe. The LHC is performing beyond expectations, and will soon enter a new era with its planned high-luminosity upgrade. Meanwhile, propelled by surprising discoveries from a series of pioneering experiments, neutrino physics has progressed dramatically, and its progress will continue with new and innovative experiments. Intense kaon and muon beams, and SuperKEKB, will provide excellent opportunities to search for new physics in different ways, and will help to inform future research directions. Diverse approaches to probe the nature of dark matter and dark energy are also on their way. While we cannot know what will be the headline results at the next ICHEP event – which will be held in 2018 in Seoul, South Korea – we can be certain that surprises are in store.
La protonthérapie est une technique de radiothérapie innovante, qui peut traiter des tumeurs avec beaucoup plus de précision que les rayons X ou les rayons gamma. Le nombre de centres de traitement par protonthérapie augmente rapidement, et offre aux patients des traitements plus efficaces avec un risque de complications moindre. Au Centre Antoine Lacassagne, à Nice, une nouvelle installation de protonthérapie de haute énergie, qui tire son origine d’une collaboration avec le CERN vieille de 30 ans, se prépare à présent à traiter son premier patient. À performance égale, son accélérateur est quatre fois plus léger et consomme huit fois moins d’énergie que les machines actuelles, et il peut traiter tous types de tumeurs situées profondément à l’intérieur du corps humain.
Each year, millions of people worldwide undergo treatment for cancer based on focused beams of high-energy photons. Produced by electron linear accelerators (linacs), photons with energies in the MeV range are targeted on cancerous tissue where they indirectly ionise DNA atoms and therefore reduce the ability of cells to reproduce. Photon therapy has been in clinical use for more than a century, following the discovery of X-rays by Roentgen in 1896, and has helped to save or improve the quality of countless lives.
Proton therapy, which is a subclass of particle or hadron therapy, is an innovative alternative technique in radiotherapy. It can treat tumours in a much more precise manner than X- or gamma-rays because the radiation dose of protons is ballistic: protons have a definite range characterised by the Bragg peak, which depends on their energy. This initial ballistic advantage gives protons their advantage over X-rays to provide a dose deposition that better matches tumour contours while limiting the dose in the vicinity. This property, which was first identified by accelerator-pioneer Robert Wilson in 1946 when he was involved in the design of the Harvard Cyclotron Laboratory, results in a greater treatment efficiencyand a lower risk of complications.
The pioneers of proton therapy used accelerators from physics laboratories at locations including Uppsala in Sweden in 1957; Boston Harvard Cyclotron Laboratory in the US in 1961; and the Swiss Institute for Nuclear Research in Switzerland in 1984. The first dedicated clinical proton-therapy facility, which was driven by a low-energy cyclotron, was inaugurated in 1989 at the Clatterbridge Centre for Oncology in the UK. The following year, a dedicated synchrotron designed at Fermilab began operating in the US at the Loma Linda University Medical Center in California. By the early 2000s, the number of treatment centres had risen to around 20, and today proton therapy is booming: some 45 facilities are in operation worldwide, with around 20 under construction and a further 30 at the planning stage in various countries around the world (see www.ptcog.ch).
Towards MEDICYC
Modern proton therapy exploits an active technique called pencil-beam scanning, which creates a pointillist 3D tumour-volume painting by displacing the proton beam with appropriate magnets. Moreover, different irradiation ports are generally possible thanks to rotating gantries. This delivery technique is competitive with the most advanced forms of X-ray irradiation, such as intensity-modulated radiation therapy (IMRT), tomotherapy, cyberknifeand others, because it uses a smaller number of entering ports and hence reduces the overall absorbed dose to the patient.
Owing to its high dose accuracy, proton therapy has historically been oriented towards the treatment of uveal melanoma and base-of-skull tumours, for which X-rays are less efficient. Today, however, proton therapy is used to treat any tumour type with a predilection for paediatric treatment. Indeed, by limiting the integral dose to an absolute minimum at the whole-body level, the side effects of radiotherapy occurring from radiation-induced cancer are reduced to a minimum.
Particle physics, and CERN in particular, has played a key role in the success of proton therapy. One of the first facilities operating in Europe was MEDICYC – a 65 MeV proton medical cyclotron that was initially devoted to neutron production for cancer therapy. It was installed at the Centre Antoine Lacassagne (CAL) in Nice in 1991, where the first proton-therapy treatment for ocular melanoma was achieved in France. MEDICYC was designed by a small team of young CAL members hosted by CERN in the PS division, and the advice of the passionate experts there was key to the success of this accelerator. Preliminary studies for MEDICYC and the first test of the radiofrequency accelerating system were performed at CERN. Indeed, because the cyclotron was completed before the building that would house it, it was proposed to assemble the cyclotron magnet at CERN in the East Hall of the PS division, to perform the magnetic-measurement campaigns.
During its 25 year operational lifetime, which began in June 1991, MEDICYC has reached a high level of reliability and successfully treated more than 5500 patients for various ocular tumours with a 96% local control rate. Owing to its high-dose-profile quality (0.8 mm dose fall-off beyond the Bragg peak, which is of the utmost importance for irradiating tumours close to the optical nerve), MEDICYC will continue to run its medium-energy proton-therapy programme. Moreover, CAL is investigating a MEDICYC improvement programme for increasing the beam intensities in view of new medical-isotope production at high energies with protons and deuterons.
On 30 June this year, a new proton therapy centre called the Institut Méditerranéen de Protonthérapie (IMPT) was inaugurated at CAL, marking a new phase in European advanced hadron therapy. Joining MEDICYC as the driver of this new facility is a new cyclotron called the Superconducting Synchro-cyclotron (S2C2). This facility, which will expand the proton-therapy activity of MEDICYC, uses the latest technology to precisely target tumours while controlling the intensity and spatial distribution of the dose with fine precision. It is therefore ideal for treating base of skull, head and neck, sarcomas tumours and with priority oncopediatics tumours, and is expected to treat up to 250 patients per year in its first phase.
CERN beginnings
The new facility at CAL has its roots in a CERN-led project called EULIMA (European Light Ions Medical Accelerator) – a joint initiative at the end of the 1980s to bring the potential benefit of hadron therapy with light ions to cancer patients in Europe. Historically, CAL was involved with several European institutes to undertake feasibility studies for EULIMA. The feasibility study group was hosted by CERN and the main design option for the accelerator was a four-magnetic-sector cyclotron with a single large cylindrical superconducting excitation coil designed by CERN magnet-specialist Mario Morpurgo. CAL was selected as a candidate site to host the EULIMA prototype because it offered both adequate space in the MEDICYC building to house the machine and treatment rooms, while also offering an adequate supply of medical, scientific and technical staff in an attractive site.
When the EULIMA came to an end in 1992, the empty EULIMA hall was available for future development projects in high-energy proton therapy. Therefore, in 2011, we were able to construct the new S2C2 facility at CAL at low cost. This compact, approximately 40 tonne facility provides proton beams with an energy of 230 MeV and delivers its dose using dynamic pencil-beam scanning (PBS). Its design is the result of a collaboration between AIMA (a spin-out company from CAL) and Belgian medical firm IBA.
The facility comprises a beamline that feeds an R&D room for research teams, which have decided to commit themselves to a national research programme called France Hadron. The programme gathers several hadron-therapy centres based at Paris-Orsay, Lyon, Caen, Toulouse and Nice, in addition to several universities and national public research institutions, to co-ordinate and organise a national programme of research and training in hadron therapy. This programme aims at bringing nuclear-physics techniques to clinical research through dosimetry, radiation biology, imaging, control of target positioning, and quality-control instruments.
As is the case for eye treatment at MEDICYC, the new facility will operate in co-operation with the Léon Bérard cancer centre in Lyon and other oncologic centres in the south of France. The new high-energy proton facility displays many innovative technological breakthroughs compared with existing systems. The accelerator is four-times lighter and consumes eight-times less energy than current machines for the same performance, and its maximum energy of 230 MeV can treat all tumours deep in the human body up to a depth of 32 cm. Its significantly lower cost represents a particularly attractive alternative compared with the global industrial standard. It also foreshadows a major development of proton therapy in the coming years, because compact synchrocyclotron technology is also being developed for the acceleration of alpha particles and heavier ions for hadron therapy.
A major innovation is its rotating compact gantry, the first prototype of which was installed in the US in 2013. The new beamline has a mobility that allows operators to direct the radiation beam in different incidences around the patient and offer unprecedented compactness, reducing costs further. The new S2C2 and the future upgrading programme of MEDICYC embody the medical mission of CAL at large by bringing together advanced proton therapy for treating patients and scientific research activities with multidisciplinary teams of medical physicists and radiobiologists.
Le CERN produira des radio-isotopes pour la médecine
Le lien entre les communautés des accélérateurs et de la médecine remonte à presque 50 ans. Aujourd’hui, alors que les physiciens développent la nouvelle génération de machines pour la recherche, les médecins imaginent de nouvelles méthodes pour diagnostiquer et traiter les maladies neurodégénératives et les cancers. Le projet MEDICIS du CERN vise à développer de nouveaux isotopes pouvant être utilisés à la fois comme agents de diagnostic et pour la curiethérapie ou la radiothérapie interne avec source non scellée, pour le traitement de cancers du cerveau ou du pancréas non opérables et d’autres formes de cette maladie. L’installation, dont l’idée a germé en 2010 et qui sera opérationnelle en 2017, utilise un faisceau de protons et l’installation de faisceaux d’ions radioactifs ISOLDE pour produire des isotopes médicaux. Ces isotopes seront d’abord destinés à des hôpitaux et des centres de recherche en Suisse, puis progressivement à d’autres laboratoires en Europe et ailleurs dans le monde.
Accelerators and their related technologies have long been developed at CERN to undertake fundamental research in nuclear physics, probe the high-energy frontier or explore the properties of antimatter. Some of the spin-offs of this activity have become key to society. A famous example is the World Wide Web, while another is medical applications such as positron emission tomography (PET) scanner prototypes and image reconstruction algorithms developed in collaboration between CERN and Geneva University Hospitals in the early 1990s. Today, as accelerator physicists develop the next-generation radioactive beam facilities to address new questions in nuclear structure – in particular HIE-ISOLDE at CERN, SPIRAL 2 at GANIL in France, ISOL@Myrrha at SCK•CEN in Belgium and SPES at INFN in Italy – medical doctors are devising new approaches to diagnose and treat diseases such as neurodegenerative disorders and cancers.
The bridge between the radioactive-beam and medical communities dates back to the late 1970s, when radioisotopes collected from a secondary beam at CERN’s Isotope mass Separator On-Line facility (ISOLDE) were used to synthesise an injectable radiopharmaceutical in a patient suffering from cancer. 167Tm-citrate, a radiolanthanide associated to a chelating chemical, was used to perform a PET image of a lymphoma, which revealed the spread-out cancerous tumours. While PET became a reference protocol to provide quantitative imaging information, several other pre-clinical and pilot clinical tests have been performed with non-conventional radioisotopes collected at radioactive-ion-beam facilities – both for diagnosis and for therapeutic applications.
Despite significant progress made in the past decade in the field of oncology, however, the prognosis of certain tumours is still poor – particularly for patients presenting advanced glioblastoma multiforme (a form of very aggressive brain cancer) or pancreatic adenocarcinoma. The latter is a leading cause of cancer death in the developed world and surgical resection is the only potential treatment, although many patients are not candidates for surgery. Although external-beam gamma radiation and chemotherapy are used to treat patients with non-operable pancreatic tumours, and survival rates can be improved by combined radio- and chemotherapy, there is still a clear need for novel treatment modalities for pancreatic cancer.
A new project at CERN called MEDICIS aims to develop non-conventional isotopes to be used as a diagnostic agent and for brachytherapy or unsealed internal radiotherapy for the treatment of non-resectable brain and pancreatic cancer, among other forms of the disease. Initiated in 2010, the facility will use a proton beam at ISOLDE to produce isotopes that first will be destined for hospitals and research centres in Switzerland, followed by a progressive roll-out to a larger network of laboratories in Europe and beyond. The project is now approaching its final phase, with start-up foreseen in June 2017.
A century of treatment
The idea of using radioisotopes to cure cancer was first proposed by Pierre Curie soon after his discovery of radium in 1898. The use of radium seduced many physicians because the penetrating rays could be used superficially or be inserted surgically into the body – a method called brachytherapy. The first clinical trials took place at the Curie Institute in France and at St Luke’s Memorial Hospital in New York at the beginning of the 20th century, for the treatment of prostate cancer.
A century later, in 2013, a milestone was met with the successful clinical trials of 223Ra in the form of the salt-solution RaCl2, which was injected into patients suffering from prostate cancers with bone metastasis. The positive effect on patient survival was so clear in the last clinical validation (so-called phase III), that the trial was terminated prematurely to allow patients who had received a placebo to be given the effective drug. Today, the availability of new isotopes, medical imagery, robotics, monoclonal antibodies and a better understanding of tumour mechanisms has enabled progress in both brachytherapy and unsealed internal radiotherapy. Radioisotopes can now be placed closer to and even inside the tumour cells, killing them with minimal damage to healthy tissue.
CERN-MEDICIS aims to further advance this area of medicine. New isotopes with specific types of emission, tissue penetration and half-life will be produced and purified based on expertise acquired during the past 50 years in producing beams of radioisotope ions for ISOLDE’s experimental programme. Diagnosis by single photon emission computed tomography (SPECT), a form of scintigraphy, covers the vast majority of worldwide isotope consumption based on the gamma-emitting 99mTc, which is used for functional probing of the brain and various other organs. PET protocols are increasingly used based on the positron emitter 18F and, more recently, a 68Ga compound. Therapy, on the other hand, is mostly carried out with beta emitters such as 131I, more recently with 177Lu, or with 223Ra for the new application of targeted alpha therapy. Other isotopes also offer clear benefits, such as 149Tb, which is the lightest alpha-emitting radiolanthanide and also combines positron-emitting properties.
Driven by ISOLDE
With 17 Member States and an ever-growing number of users, ISOLDE is a dynamic facility that has provided beams for around 300 experiments at CERN in its 50 year history. It allows researchers to explore the structure of the atomic nucleus, study particle physics at low energies, and provides radioactive probes for solid-state and biophysics. Through 50 years of collaboration between the technical teams and the users, a deep bond has formed, and the facility evolves hand-in-hand with new technologies and research topics.
CERN MEDICIS is the next step in this adventure, and the user community is joining in efforts to push the development of the machine in a new direction. The project was initiated six years ago by a relatively small collaboration involving CERN, KU Leuven, EPFL and two local University Hospitals (CHUV in Lausanne and HUG in Geneva). One year later, in 2011, CERN decided to streamline medical production of radioisotopes and to offer grants dedicated to technology transfer. While the mechanical conveyor system to transport the irradiated targets was covered by such a grant, the construction of the CERN MEDICIS building began in September 2013. The installation of the services, mass separator and laboratory is now under way.
At ISOLDE, physicists direct a high-energy proton beam from the Proton Synchrotron Booster (PSB) at a target. Since the beam loses only 10% of its intensity and energy on hitting the target, the particles that pass through it can still be used. For CERN-MEDICIS, a second target therefore sits behind the first and is used for exotic isotope generation. Key to the project is a mechanical system that transports a fresh target and its ion source into one of the two ISOLDE target-stations’ high resolution separator (HRS) beam dump, irradiates it with the proton beam from the PSB to generate the isotopes, then returns it to the CERN-MEDICIS laboratory. The system was fully commissioned in 2014 under proton-beam irradiation with a target that was later used to produce a secondary beam, thus validating the full principle. A crucial functional element was still missing: the isotope mass separator, along with its services and target station. Coincidentally, however, CERN MEDICIS started just as the operation of KU Leuven’s isotope-separation facility ended, and a new lease of life could therefore be given to its dipole magnet separator, which was delivered to CERN earlier this year for testing and refurbishment.
A close collaboration is growing at MEDICIS centred around the core team at CERN but involving partners from fundamental nuclear physics, material science, radiopharmacy, medical physics, immunology, radiobiology, oncology and surgery, with more to come.
Training network
With such an exceptional tool at hand, and based on growing pre-clinical research experiments performed at local university hospitals, in 2014 a H2020 Innovative Training Network was set up by CERN to ensure MEDICIS is fully exploited. This “Marie Skłodowska-Curie actions” proposal was submitted to the European Commission entitled MEDICIS-Promed, which stands for MEDICIS-produced radioisotope beams for medicine. The goal of this 14-institution consortium is to train a new generation of scientists to develop systems for personalised medicine combining functional imaging and treatments based on radioactive ion-beam mass separation. Subsystems for the development of new radiopharmaceuticals, isotope mass separators at medical cyclotrons, and of mass-separated 11Carbon for PET-aided hadron therapy are to be specifically developed to treat ovarian cancer. Pre-clinical experiments have already started, with the first imaging studies ever done with these exotic radioisotopes. For this, a specific ethical review board has been implemented within the consortium and is chaired by independent members.
With the MEDICIS facility entering operation next year, an increasing range of innovative isotopes will progressively become accessible. These will be used for fundamental studies in cancer research, for new imaging and therapy protocols in cell and animal models, and for pre-clinical trials – possibly extended to early phase clinical studies up to Phase I trials. During the next few years, 500 MBq isotope batches purified by electromagnetic mass separation combined with chemical methods will be collected on a weekly basis. This is a step increase in production to make these innovative isotopes more available to biomedical research laboratories, compared with the present production of a few days per year in a facility such as ISOLDE.
Staged production
During its initial stage in 2017, only low-Z materials, such as titanium foils and Y2O3 ceramics, will be used as targets. From these, we will produce batches of several hundred MBq of 44,47Sc and 61,64Cu. In the second stage, tentatively scheduled for 2018, we will use targets from the nuclei of higher atomic numbers, such as tantalum foils, to reach some of the most interesting terbium and lanthanide isotopes. In a final phase in 2018, we foresee the use of uranium and thorium targets to reach an even wider range of isotopes and most of the other alpha-emitters.
Selected isotopes will first be tested in vitro for their capacity to destroy glioblastoma or pancreatic adenocarcinoma or neudoendocine tumour cells, and in vivo by using mouse models of cancer. We will also test the isotopes for their direct effect on tumours and when they are coupled to peptides with tumour-homing capacities. New delivery methods for brachytherapy using stereotactic, endoscopic ultrasonographic-guided or robotic-assisted surgery will be established in large-animal models.
Moreover, this new facility marks the entrance of CERN into the era of theranostics. This growing oncological field allows nuclear-medicine physicians to verify and quantify the presence of cellular and molecular targets in a given patient with the diagnostic radioisotope, before treating the disease with the therapeutic radioisotope. The prospect of a dedicated facility at CERN for the production of innovative isotopes, together with local leading institutes in life and medical sciences and a large network of laboratories, makes this an exciting scientific programme in the coming years.
The mission of the US Department of Energy (DOE) isotope programme is to produce and distribute radioisotopes that are in short supply and in high demand for medical, industrial and environmental uses. The DOE programme also maintains the unique infrastructure of national laboratories across the country, one of which is Brookhaven National Laboratory’s medical radioisotope programme, MIRP. Although there are many small accelerators in the US that produce radioisotopes, the availability of proton energies up to 200 MeV from the Brookhaven Linac Isotope Producer (BLIP) is unique.
There is significant promise for treating a variety of diseases including metastatic cancer, viral and fungal infections and even HIV
Radioisotopes are of interest both for nuclear medicine and for diagnostic imaging and therapy. The most important aspect of Brookhaven’s isotope programme is the large-scale production and supply of clinical-grade strontium-82 (82Sr). Although 82Sr is not directly used in humans, its short-lived daughter product 82Rb is a potassium mimic and upon injection is rapidly taken up by viable cardiac tissue. It is therefore supplied to hospitals as a generator for positron emission tomography (PET) scans of the heart, where its short half-life (76 seconds) allows multiple scans to be performed and minimal doses delivered to the patient. At present, up to 350,000 patients per year in the US receive such PET scans, but demand is growing beyond capacity.
There is also significant promise for the utilisation of alpha emitters for treating a variety of diseases including metastatic cancer, viral and fungal infections and even HIV, for which the leading candidate is the alpha-emitter 225Ac. Thanks to a series of upgrades completed this year, Brookhaven is now in a position to boost production of both of these vital medical isotopes.
Protons on target
The BLIP was built in 1972 and was the world’s first facility to utilise high-energy, high-current protons for radioisotope production. It works by diverting the excess beam of Brookhaven’s 200 MeV proton linac to water-cooled target assemblies that contain specially engineered targets and degraders to allow optimal energy to be delivered to the targets. The use of higher-energy particles allows relatively thick targets to be irradiated, in which the large number of target nuclei compensate for the generally smaller reaction cross-sections compared to low-energy nuclear reactions.
Although the maximum proton energy is 200 MeV, lower energies can be delivered by sequentially turning off the accelerating sections to achieve 66, 92, 117, 139, 160, 181 and 200 MeV beams. This is the only linac with such a capability, and its energy and intensity can be controlled on a pulse-by-pulse basis. As a result, the linac can simultaneously supply high-intensity pulses to the BLIP and a low-intensity polarised proton beam to the booster synchrotron for injection into the Alternating Gradient Synchrotron (AGS) and the Relativistic Heavy Ion Collider (RHIC) for Brookhaven’s nuclear-physics programme. This shared use allows for cost-effective operation. The BLIP design also enables bombardment of up to eight targets, offering the unique ability to produce multiple radioisotopes at the same time (see table). Target irradiations for radiation-damage studies are also performed, including for materials relevant to collimators used at the LHC and Fermilab.
The Gaussian beam profile of the linac results in very high power density in the target centre. Until recently, the intensity of the beam was limited to 115 μA to ensure the survival of the target. This year, however, a raster system was installed that allows the current on the target to be increased by allowing a more uniform deposition of the beam across the target. This system requires rapid cycling magnets and power supplies to continuously move the beam spot, and has been fully operational since January 2016.
Production of 82Sr is accomplished by irradiating a target comprising rubidium-chloride salt with 117 MeV protons, with the raster parameters driven by the thermal properties of the target. This demanded diagnostic devices in the BLIP beamline that enable the profile of the beam spot to be measured, both for initial device tuning and commissioning and for routine monitoring. These included a laser-profile monitor, beam-position monitor and plunging multi-wire devices. It was also necessary to build an interlock system to detect raster failure, because the target could be destroyed rapidly if the smaller-diameter beam spot stopped moving. The beam is moved in a circular pattern at a rate of 5 kHz with two different radii to create one large and one smaller circle. The radius values and the number of beam pulses for each radius can be programmed to optimise the beam distribution, allowing a five-fold reduction in peak power density.
Given the resulting increase in current from these upgrades, a parallel effort was required to increase the linac-beam intensity. This was accomplished by extending the present pulse length by approximately five per cent and optimising low-energy beam-transport parameters. These adjustments have now raised the maximum beam current to 173 μA, boosting radioisotope production by more than a third. After irradiation, all targets need to be chemically processed to purify the radioisotope of interest from target material and all other coproduced radioisotopes, which is carried out at Brookhaven’s dedicated target-processing laboratory.
Tri-lab effort
Among the highest-priority research efforts of the MIRP is to assess the feasibility of using an accelerator to produce the alpha emitter 225Ac. Alpha particles impart a high dose in a very short path length, which means that high doses to abnormal diseased tissues can be delivered while limiting the dose to normal tissues. Although there have been several promising preclinical and clinical trials of alpha emitters in the US and Europe, the 10 day half-life of 225Ac would enable targeted alpha radiotherapy using large proteins such as monoclonal antibodies and peptides for selective treatments of metastatic disease. 225Ac decays through multiple alpha emissions to 213Bi, which is an alpha emitter with a half-life of 46 minutes and can therefore be used with peptides and small molecules for rapid targeted alpha therapy.
Although 225Ac is the leading-candidate alpha emitter, vital research has been hindered by its very limited availability. To accelerate this development, a formal “Tri-Lab” collaboration has been established between BNL and two other DOE laboratories: Los Alamos National Laboratory (LANL) and Oak Ridge National Laboratory (ORNL). The aim is to evaluate the feasibility of irradiating thorium targets with high-energy proton beams to produce much larger quantities of 225Ac for medical applications. Because there is a direct correlation between beam intensity and radioisotope yields, the higher the intensity the higher the yield of these and other useful isotopes. So far, BNL and LANL have measured cross-sections, developed and irradiated relevant alpha-emitter targets for shipment to ORNL and other laboratories. These include several targets containing 225Ac-radioactivity up to 5.9 GBq and others for chemical and biological evaluation of both direct 225Ac use as well as use of a generator to provide the shorter-lived 213Bi. Similar irradiation methods are available at LANL and also TRIUMF in Canada.
Irradiation of thorium metal at high energy also creates copious fission products. This complicates the chemical purification but also creates an opportunity because some coproduced radiometals are of interest for other medical applications. The BNL group therefore plans to develop and evaluate methods to extract these from the irradiated-thorium target in a form suitable for use. In addition to 225Ac, the BNL programme is evaluating the future production of other radioisotopes that can be used as “theranostics”. This term refers to isotope pairs or even the same radioisotope that can be used for both imaging and therapeutic applications. Among the potentially attractive isotopes for this purpose that can be produced at BLIP are the beta- and gamma-emitters 186Re and 47Sc.
BNL has served as the birthplace for nuclear medicine from the 1950s, and saw the first use of high-intensity, high-power beams for radioisotope production. Under the guidance of the DOE isotope programme, the laboratory is using its unique accelerator facilities to develop and supply radioisotopes for imaging and therapy. Completed and future upgrades will enable large-scale production of alpha emitters and theranostics to meet presently unmet clinical need. These will enable personalised patient treatments and overall improvements in patient health and quality of life.
External-beam radiation therapy is used routinely to treat many different types of cancerous tumours, delivering a targeted dose of radiation to cancer cells while sparing surrounding healthy tissue as much as possible. While there have been dramatic improvements in the control of patient and tumour dose during recent years, many challenges persist. These include side effects such as depressed immunity, which makes patients susceptible to post-treatment infections, and an increase in secondary cancers.
An alternative approach involves delivering a therapeutic radiation dose to tumour cells selectively through a strategy similar to that for molecular imaging: therapeutic isotopes are incorporated into complex pharmaceuticals for specific, targeted delivery of a potent radiation dose directly to cancerous cells. This approach has been recognised since the time of Madame Curie, but even after a century of development, this application remains woefully unoptimised.
To study the full potential of radionuclide therapy, the medical research community is increasingly demanding therapeutic alpha- and beta-emitting isotopes to treat advanced metastatic cancer and other diffuse diseases. Such therapeutic isotopes are changing the cancer-treatment landscape, yet lack of availability and cost are significantly affecting further research and development.
Targeted radionuclide therapy
Targeted radionuclide therapy (TRT) involves the injection of particle-emitting radionuclides appended to a biological targeting molecule, which direct a lethal dose of radiation to a specific site within the body. The short range and highly cytotoxic nature of alpha and beta particles destroys small, diffuse and post-operative residual tumours while minimising damage to healthy tissue. TRT’s strength lies in the diversity and adaptability of both isotopes and targeting molecules, which include monoclonal antibodies, antibody fragments, nanoparticles, and small peptides and molecules. Because this allows an optimal delivery regimen to be developed for each application, TRT isotopes are generating significant interest internationally.
Within the Life Sciences Division of TRIUMF in Vancouver, Canada, TRT is now an active research effort. The goal is to exploit TRIUMF’s production and radiochemistry capabilities to enable fundamental and applied research with a spectrum of isotopes across different disciplines. In the near-to-medium term, TRIUMF plans to develop platform technologies to enable accelerator-based radiometallic isotope production and applications beyond the current state-of-the-art. Access to a host of metallic isotopes will allow TRIUMF to leverage its radiochemistry expertise to demonstrate the synthesis of novel radiopharmaceuticals, including TRT drugs.
Targeted alpha therapy (TAT) is a type of TRT that exploits the high linear-energy transfer of alpha particles (figure 1) to maximise tumour-cell destruction while minimising damage to surrounding cells. As such, TAT has tremendous potential to become a very powerful, selective tool for personalised cancer treatments. To fulfil its promise, however, TAT relies heavily on new developments in isotope production. It also demands organic, bioinorganic and organometallic synthesis techniques to create new molecular probes, and novel techniques to address the stability of metal complexes in vivo.
Several promising alpha-emitting radionuclides are currently under consideration worldwide – including 149Tb, 211At, 212Bi, 212Pb,213Bi, 223Ra, 225Ac, 226Th and 230U – and very promising results have already emerged from clinical and pre-clinical studies of TAT agents. Progress at several laboratories is fuelling great optimism in the medical community. For example, the US Food and Drug Administration recently approved the use of the alpha emitter 223RaCl2 (registered under the trademark Xofigo) for pain relief from bone metastases, and several other TAT drugs are in the clinical-trial pipeline.
Securing a constant supply of clinically relevant amounts of alpha-emitting radionuclides remains a challenge, since their production requires high-Z targets and a complex infrastructure. “Generator systems” are a convenient source of TAT isotopes: for example, 225Ac (which has a half-life of 9.92 days) can be harvested as a decay product of 229Th. Because the global quantity of 229Th is not being replenished and the 229Th/225Ac generator can only be eluted every nine weeks, annual worldwide production is limited to approximately 1.7 curies. Several alternative strategies are therefore being proposed to produce such isotopes directly.
TAT radionuclides must be carefully processed before being used in medical applications. They first must be isolated with high radio-chemical purity from the target material, which can be achieved using classical chemical procedures such as ion exchange, extraction and precipitation. Purified TAT radionuclides are then attached to biomolecule targeting vectors via a bifunctional chelator, which connects the biomolecule with a radionuclide complex (figure 2). The stability of compounds containing alpha-emitting radionuclides is a challenge because after decay most of the daughter isotopes are radioactive elements that no longer remain chelated. Moreover, the radioactive daughters can accumulate and cause unwanted toxicity in healthy organs, especially those involved in excretion such as the liver and kidneys. These issues have driven demand for a more robust and stable chelation system and/or encapsulation methods that contribute to an optimised pharmacokinetic profile with rapid cell internalisation. By doing so, the hope is to keep radioactive daughter nuclei proximal to the original decay site and thus close to the targeted tissue.
Several clinical trials with alpha-emitting radionuclides – including 225Ac (phase II trial) and 213Bi (phase III) – are under way around the world, based on the standard chelation approach. Despite the challenges involved, these trials are already showing extremely high promise and superiority over existing beta-emitting radionuclides. Further research is therefore warranted to investigate and optimise various production strategies designed to make TAT a viable clinical modality. The TAT isotope 225Ac has demonstrated particularly high potential in recent years because its half-life correlates well with the biological half-lives of intact antibodies, and its multiple alpha-emitting daughters enhance the therapeutic effect. 225Ac also can be used as a parent radionuclide for a 225Ac/213Bi generator system.
TRIUMF’s strategy
TRIUMF has extensive expertise in all aspects of the production of medical isotopes, including the development of high-powered targets for large-scale production and expertise in isotope-production simulations with its existing Monte Carlo code FLUKA and the new Geant4. TRIUMF’s strategy involves using both existing and new proton beamlines from its 520 MeV cyclotron, along with a newly built 30 MeV electron linac in the upcoming Advanced Rare IsotopE Laboratory (ARIEL) facility, to irradiate thorium and uranium targets to produce a variety of radiometals. These include 225Ra and 224Ra, which are parent isotopes for the daughter products 225Ac, 212,213Bi and 212Pb. Because these targets can be positioned downstream from the science targets, the symbiotic production of these radiometals is limited only by the beam intensity.
Under the envisioned operating conditions of the new proton beamline, FLUKA simulations of the ARIEL proton target station predict yields of several-hundred millicuries of 225Ac per irradiation and significant quantities of other isotopes. While only very small quantities of 225Ac are required for radionuclide therapy, larger quantities are required to produce enough 213Bi in those treatments where it’s preferred. A larger demand for 213Bi will then drive a similarly increased demand for 225Ac to provide adequate 225Ac/213Bi generators. Thus, TRIUMF’s emerging production capacity would yield sufficient 225Ac to enable the assembly of multiple 225Ac/213Bi generators for therapeutic research studies in patients at multiple centres. Based on typical operating-schedule estimates, this technique could result in the production of several curies of 225Ac per year, compared to the current global output of 1 to 2 curies per year, making the proposed infrastructure a potentially potent source of this valuable isotope. Furthermore, many other medically relevant radioisotopes apart from 225Ac are produced from a thorium or uranium target. The higher current proton beam at ARIEL will enable TRIUMF researchers to explore this exciting medical isotope further.
The ultimate goal of TRIUMF’s TRT programme is to carry out clinical testing and establish the efficacy of TRT agents, enabling a national and possibly international clinical-trial programme for promising therapeutics. TRIUMF research partners will develop new radiopharmaceuticals incorporating therapeutic nuclei into targeting molecules, producing therapeutic conjugates that are used to shepherd their targeted payload to tumours. In addition, research will be carried out to design new molecules that can be used to target different types of tumours.
By leveraging TRIUMF’s existing infrastructure and established research partnerships, the medical community can look forward to production of higher quantities of TRT isotopes. Should the promising results seen to date materialise into a viable treatment option for late stage and/or currently untreatable cancers, the results will bring new hope for a significant number of cancer patients worldwide.
Nuclear reactors are usually thought of in the context of electricity generation, whereby heat generated by nuclear fission produces steam to drive an alternator. A less well-known class of nuclear-fission reactors fulfils an entirely different societal goal. Known as research and test reactors, the heat they produce is a by-product, while the neutrons resulting from the fission reactions are used to irradiate materials or as probes for materials science. In some reactors, neutrons are used to transmute stable isotopes into radioactive ones, which are subsequently utilised for industrial or medical purposes.
Used in diagnostics and treatment, medical radioisotopes are a vital tool in the arsenal of oncologists in detecting and fighting cancer. In the case of 99mTc, which is a daughter product of 99Mo, roughly 30 million patients per year are injected with this isotope. This accounts for 80% of all nuclear-medicine diagnostic procedures, and demand is only growing as more of the global population gain access to advanced medicine. Classically, 99Mo is produced as a fission product in uranium targets: after irradiation lasting around one week, the targets are rushed off to the processing facility where the 99Mo is extracted. Since its half-life is only around six days, there is no way to stock up on the isotope, and therefore a continuous chain of target production, irradiation, isotope extraction and purification – and finally supply to hospitals – is required.
The importance of a steady supply of medical radioisotopes such as 99Mo cannot be overestimated, yet it is generally not possible to cover the cost of operating a large research reactor or other facility solely for the production of radioisotopes, and the yield needs to be sufficiently high for such a production to even significantly reduce the cost. Traditionally, the economics of constructing an accelerator facility for the sole purpose of generating 99Mo have been challenging, especially since the fission yield of 99Mo outweighs the possible yields from non-reactor methods by at least a factor of 10. Recently, however, a reduction in the construction costs of high-power accelerators and the increasing costs associated with operating reactors has generated interest in accelerator-based production of 99Mo, for example via semi-commercial initiatives such as SHINE and NorthStar in the US.
One of the driving forces behind these developments is the ageing of existing research reactors. The global supply of 99Mo mainly originates in a handful of reactors such as the BR2 in Belgium, the NRU in Canada or the HFR in the Netherlands, and most of them are more than 50 years old. The NRU, which alone is responsible for about a third of the global demand of 99Mo, is scheduled to cease production this year. Some reactors are still planned to continue operation for multiple decades (such as OPAL in Australia, SAFARI in South Africa and BR2), while smaller research reactors such as MARIA in Poland and LVR-15 in the Czech Republic are getting increasingly involved in radioisotope production and new research reactors are being contemplated: MYRRHA in Belgium, PALLAS in the Netherlands and JHR in France (for which construction is ongoing), for instance. Despite these developments, it is uncertain if the rising demand can continue to be met without assistance from accelerator-based production.
Neutrons are very suitable for isotope production because the cross-sections for neutron-induced nuclear reactions are often much larger than those for charged particles. As such, there is an advantage in using the neutrons already available at research reactors for isotope production. But it is clear that accelerators and reactors are highly complementary. Reactors generate neutron-rich isotopes through fission or activation, whereas accelerators typically allow the production of proton-rich isotopes. Alpha emitters are also becoming more popular in nuclear medicine, particularly in palliative care, and the role of accelerators will likely become more important in the future production of such isotopes. It is therefore healthy to maintain multiple production routes open for such vital and rare products, on which people’s lives can depend.
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