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LATTICE radiotherapy plus immunotherapy shows promise for treating advanced bulky tumours

The combination of LATTICE radiation therapy (LRT), a spatially fractionated radiotherapy technique, and immunotherapy dramatically shrank a large metastatic lung cancer mass in one month and resulted in a complete local response within five months, according to a case report in Frontiers in Oncology. The patient, a woman with advanced non-small cell lung cancer and multiple metastases, did not experience any side effects from the high radiation dose she received. The dramatic effectiveness of this combined treatment is spearheading the development of future clinical studies.

Bulky tumours are challenging to treat using radiotherapy due to large tumour sizes and limitations of normal tissue toxicity. Spatially fractionated techniques such as high-dose 2D grid radiotherapy and LRT – a 3D lattice-like reconfiguration of grid therapy – have been employed to safely treat bulky tumours. LRT uses multiple high-dose regions (vertices), distributed within the tumour volume according to its size and shape and the proximity of critical structures, with valleys of much lower dose in between.

The technique’s principal developer, Xiaodong Wu from Executive Medical Physics Associates in Miami, FL, explains that when 3D LRT is delivered using intensity-modulated radiation therapy, volumetric modulated arc therapy or ion beams, highly customized peak-to-valley dose distributions can be generated within the tumour volume, while sparing skin and normal tissue.

Xiaodong Wu and Benhua Xu — Researchers Xiaodong Wu (left) and Benhua Xu.

LRT is currently used for palliative tumour debulking or boost treatments and to safely deliver high radiation doses to partial volumes of large tumours. It can be administered alone or in combination with conventionally fractionated radiotherapy.

Led by Benhua Xu, chief of the Department of Radiation Oncology at Fujian Medical University Union Hospital in China, this case study represents the first use of LRT in conjunction with immune checkpoint blockade – a treatment that help the body’s immune system recognize and attack cancerous cells.

The 33-year old patient was diagnosed with advanced invasive adenocarcinoma in the lower lobe of her right lung. Within months following surgery and chemotherapy, she had developed multiple metastases in both lungs, the thyroid, the spine and on the posterior chest wall. While the patient was receiving checkpoint inhibitor therapy, the metastatic mass in the posterior chest wall grew from 2.0 to 63.2 cm³, with maximum dimensions of 5.0 x 5.4 x 5.3 cm.

The team administered a single fraction of LRT (20 Gy prescribed to six high-dose vertices) to this fast-growing mass. The patient continued checkpoint inhibitor therapy, receiving six cycles over the next six months. She also underwent stereotactic body radiotherapy to treat multiple metastases and received drug therapies.

Although all of the patient’s metastatic lesions responded to the various palliative treatments, only the posterior chest wall tumour that received high-dose LRT achieved a complete response. While this tumour had not responded to the initial immune checkpoint blockade (anti-PD1), after high-dose LRT, it shrank by 77.84% within a month and continued to regress until achieving complete local response five months later. There were no toxic side effects in the area of the treatment, and the site remained disease free until the patient died several months later.

The researchers note that with only 6.5% of the large tumour’s volume receiving a dose of 20 Gy and higher, the effective uniform dose was calculated as 1.2 Gy. “Based on the traditionally understood mechanism of radiobiology, the probability of achieving complete local control with such a dose for a tumour of 63 cc would be nearly zero,” they write. “The synergetic effect combining high-dose LRT with anti-PD1 becomes a plausible speculation.”

First author Toshiro Tsubouchi of Osaka University

Carbon ion grid therapy spares healthy tissue

They further hypothesize: “In high-dose LRT, the dose in the vertices are sufficiently high to induce neo-antigen release and initiate the cascade of antigen presenting cell (APC)-based T-cell priming. The dose in between the vertices is low enough to preserve internal tumour circulation/perfusion to potentially facilitate the infiltration of APCs and the primed cytotoxic T-cells. The highly heterogeneous dose configuration could reprogram the immunosuppressive tumour microenvironment to become more immunogenic, and when synergistically treated by checkpoint inhibitors, the primed T cells could attack tumour cells without being exhausted.”

Wu tells Physics World that the researchers are currently preparing systemic clinical studies using this combined treatment for patients with lung cancer, liver cancer, breast cancer and melanoma. He notes that interest in and use of LRT, and spatially fractionated radiotherapy in general, are increasing. Following the early clinical experiences primary made by Innovative Cancer Institute in Miami and Fujian Union Hospital, more institutions, including the Mayo Clinic in Rochester, have begun to offer LRT to their patients.

Strolling in the deep

At the bottom of the North Central Pacific Ocean, some 5000 m beneath the waves, lies a small, fist-sized black rock, with a knobbly surface texture, like a head of broccoli. It holds a secret at its heart – a single tooth, long ago shed by a shark swimming in the waters above. In the manner of a pearl forming around a piece of grit in an oyster, the tooth has become encapsulated by layers of waterborne minerals that settled out of the water around it. It took millions of years to reach its current size – but it shall grow no bigger.

A vast unmanned, electric submersible ploughs across the seabed like a bulldozer, heaving up our rock (among others) with its teeth, before sucking it up a hose to a ship waiting on the surface. These nodules are rich in metals like nickel, copper and cobalt – and industry has come to mine them. But the abyss is not empty, making this activity not without its victims. Our rock and its peers supported an abundance of life, from worms and starfish to crustaceans and ghost-like octopuses. As the mining machine lurches onwards, it leaves a trail of devastation in its wake – not to mention kicking up a lingering muddy cloud that chokes and smothers those survivors such as corals and sponges that are unable to flee and escape it.

Raising the alarm about this ecological vandalism against a realm about which we know precious little is the raison d’être of marine biologist Helen Scales’ beguiling new book The Brilliant Abyss: True Tales of Exploring the Deep Sea, Discovering Hidden Life and Selling the Seabed. With her light and engaging prose, Scales takes the reader on an introductory dive into the mysterious depths to reveal the myriad of life hidden within, from red and green bone-devouring worms that flourish whenever whales fall down to the abyss, to the world’s fishiest-smelling fish. There’s even a hunt for yetis – not of the elusive kind, but tiny, blind, pale crabs that survive living around deep-sea hydrothermal vents and cold seeps by farming bacteria to feast on. Like their abominable namesakes, however, they are very hairy.

As The Brilliant Abyss’ subtitle suggests, the work periodically segues into arresting tales from Scales’ career, from recovering experiments to determine what species of clams, worms and sea cucumbers colonize logs swept out to sea by floods and hurricanes, to weathering out high winds that suspended scientific activity during a research expedition in the Gulf of Mexico.

Fascinating titbits abound in Scales’ writing – including the revelation (to me, at least) that diving mammals such as whales and dolphins have evolved a special, “non-stick” form of the oxygen-carrying, haemoglobin-related protein myoglobin in their muscles. These each have a slightly negative electric charge that repels other myoglobin molecules, allowing the mammals to carry 10 times the protein that we do without the molecules clumping together and causing their bodies to go completely stiff.

Scales’ book also explores such fascinating cases as whether coronal mass ejections from the Sun could have contributed towards stranding numerous young male sperm whales in the North Sea in 2015; as well as explaining why some fish have scales that are blacker than the darkest material man has ever engineered – the multiwalled carbon nanotube, Vantablack, which is up to 99.965% absorbent. One thing that struck me while reading The Brilliant Abyss is that despite being an erstwhile student of geology and having learnt the names given to Earth’s past supercontinents, I don’t recall ever having given thought to the corresponding “superoceans” that surrounded them, such as Mirovia and Panthalassa. A shift of perspective is always fascinating.

It is perhaps in the final third of the book that Scales’ argument for the preservation of the deep from exploitation becomes most clear. She explores the medical potential of deep-sea organisms – such as sponges that harbour anti-cancer compounds – and weighs up the benefits and risks of farming the deep for food and mining it for its mineral resources, before calling for the reader to join her in campaigning for humanity to leave the deep free from excessive interference. It’s a compelling argument – although one that might perhaps have been more strongly seeded in the opening chapters of the work.

One mild disappointment of the book for me is that there are not more illustrations or pictures of the weird and wonderful creatures introduced in the text (at least in my preview copy). Scales’ descriptions may be beautifully written and highly evocative, yet a picture is, as the cliché goes, worth a thousand words. The exception is the gorgeous cover art of various deep-sea species by the artist Aaron Gregory, in a style that seems to evoke the illustrations of the German zoologist and artist Ernst Haeckel, whose work is discussed in the book.

This quibble aside, The Brilliant Abyss is a wonderfully written read that I would highly recommend – it’s the ideal plunge into the depths of Earth’s last great wilderness.

2021 Bloomsbury Sigma 352pp £16.99hb

Super Earth is astronomer’s dream for atmospheric studies

A newly discovered exoplanet called Gliese 486b could offer the best opportunity yet for studying the atmosphere of a terrestrial planet beyond the solar system. An international team, made up of astronomers at the CARMENES project and NASA’s TESS mission, showed that several aspects of Gliese 486b make it ideal for atmospheric spectroscopy. Indeed, team member Ben Montet of the University of New South Wales says, “This is the kind of planet we’ve been dreaming about for decades”. The discovery could improve our prospects for finding extrasolar atmospheres capable of supporting life.

Exoplanets orbit stars other than the Sun and in the three decades since the first one was found, the discovery of more than 4000 exoplanets have been confirmed by astronomers. Super Earths are among the most sought-after targets of all exoplanet searches. Slightly larger than Earth, these planets have stable, rocky surfaces and could have substantial atmospheres – which astronomers hope could support life in some cases.

Studying atmospheres typically involves observing how light from the exoplanet’s star is affected as it passes through the atmosphere when the exoplanet transits across the star when viewed from Earth – something that Gliese 486b does.

As this light shines through the atmosphere, certain wavelengths are absorbed by its component gases. Astronomers can use these characteristic absorption lines to determine the composition and temperature of the atmosphere. Alternatively, they can study light emitted or reflected by the planet, just before it passes behind the star.

Nearby red dwarf stars

CARMENES and TESS use complementary techniques to discover super Earths and determine whether they are suitable for further analysis. In their study, the researchers searched for exoplanets orbiting nearby red dwarf stars – which are far more likely to host rocky planets than Sun-like stars. Through their search, they detected a particularly interesting super Earth orbiting the star Gliese 486, just 26 light-years away.

The exoplanet Gliese 486b is three times the mass of Earth and 1.3 times the radius, yet it has an orbital period of just 36 hours – placing it extremely close to its star. The astronomers also predict that Gliese 486b has a surface temperature of around 430 °C – making it slightly cooler than Venus.

While these conditions may sound extreme, they are not harsh enough to strip away the exoplanet’s atmosphere. This could mean that Gliese 486b has retained some atmospheric hydrogen and helium from its initial formation. Moreover, the planet’s temperature is sufficiently high to puff out its atmosphere, without any gas escaping, making it ideal for spectroscopic studies. Indeed, the astronomers report that Gliese 486b is the best rocky planet ever discovered for studying with emission spectroscopy; and the second best for transmission spectroscopy.

Although red dwarfs are seen as strong candidates for hosting habitable exoplanets, their high levels of stellar activity also threaten to destroy their exoplanets’ atmospheres. Through further studies of Gliese 486b’s atmosphere, astronomers will be able to better assess whether the search for extrasolar life should be focused on red dwarfs.

The research is described in Science.

The development of new ionic electrolytes for energy storage devices

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Electrolyte development is a critical component in the quest for higher-performing energy storage devices. Ionic electrolytes such as ionic liquids, plastic crystals and their polymer composites can offer important safety and performance advantages over traditional molecular-solvent based systems, particularly for devices utilizing reactive metals such as lithium or sodium.

An important approach to developing ionic electrolytes that can meet the complex challenges of next-generation electrochemical devices is increasing the range of known and well-characterized electrolyte materials. Understanding how different ion structures affect the physical, thermal, electrochemical properties, and the phase behaviour when combined with Li salts, is vital to optimizing device performance.

This webinar, hosted by Jenny Pringle, will overview our recent work on the design and use of new ionic materials and their application as liquid, quasi-solid state, composite or very high Li salt content electrolytes.

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Prof. Jenny Pringle works at the Institute for Frontier Materials at Deakin University, Australia. She is a chief investigator in the ARC Centre of Excellence for Electromaterials Science (ACES) and the ARC Industrial Transformation Training Centre “StorEnergy”. She received her degree and PhD at The University of Edinburgh in Scotland, UK, before moving to Monash University, Australia, in 2002. From 2008–2012 she held an ARC QEII Fellowship, investigating the use of ionic electrolytes for dye-sensitized solar cells. Pringle moved to Deakin University in 2013. There she leads research into the development of new ionic liquids and organic ionic plastic crystals for applications including thermal energy harvesting, gas separation membranes, and lithium and sodium batteries.

Nanoparticle sensors detect arsenic in drinking water

“About 785 million people are living without access to safe and clean drinking water; 140 million people in more than 50 countries have been exposed to arsenic-contaminated water.” These were the stark opening statements from Muhammad Abbas, speaking at the recent APS March meeting.

Arsenic poisoning is one of the most significant public health concerns worldwide. Arsenic is used in semiconductors, pharmaceuticals, wood preservatives, insecticides and chicken feed, and it leaches into the groundwater. Long-term exposure can lead to cancers of the kidney, liver, lungs and skin, as well as causing skin diseases and other health issues such as hypertensive heart disease. As such, the World Health Organization and Environmental Protection Agency recommend a maximum limit of 10 µg/l arsenic in drinking water.

Despite these serious health concerns, testing for arsenic in water currently requires expensive laboratory instruments that cannot be used for on-site detection and are unsuitable for developing nations. Abbas and colleagues at LUMS in Pakistan hope to address this shortfall by designing a low-cost sensor that can detect arsenic in drinking water. “We aim to develop a sensor that’s sensitive and selective, robust and reliable, affordable, portable and easy to use for local technicians,” he said.

The sensor will be based on gold nanoparticles (AuNPs), which are excellent candidates for sensing applications as they absorb in the visible spectrum and change colour according to their size, shape and surface chemistry. To create their sensor, Abbas and colleagues coated AuNPs with dihydrolipoic acid. This coating stabilizes the nanoparticles, which form in a dispersed state in water and are wine-red in colour. Adding an electrolyte such as salt does not affect the AuNPs, which remain dispersed and stay red.

If the water contains arsenic, however, the arsenic will bind to the dihydrolipoic acid, making it unavailable to protect the AuNPs surfaces. In this scenario, adding salt causes the AuNPs to aggregate and change colour. “This aggregation is directly proportional to the amount of arsenic present, which decides the strength in the colour change,” explained Abbas, now a PhD student at the University of Texas at Dallas.

Colour change — Gold nanoparticle solutions change colour when exposed to arsenic. (Courtesy: Muhammad Abbas)

To test this approach, the team performed UV-visible spectroscopy on AuNP solutions containing different concentrations of arsenic. “We could see a visual colour change with increased amounts of arsenic, with the nanoparticles changing from red towards blue,” said Abbas. Scanning electron microscopy images of the AuNPs before and after addition of arsenic confirmed the clumping mechanism that caused the colour change.

The sensor’s detection limit was 50 µg/l (50 parts per billion) of arsenic when viewed with the naked eye, or 3 µg/l using UV-visible spectroscopy. This sensitivity is lower than that offered by existing high-tech methods, such as atomic fluorescence spectroscopy, atomic absorption spectroscopy or mass spectrometry, which can detect up to parts per trillion of arsenic. But Abbas emphasizes that these systems are costly, not portable and need trained personnel to operate them.

“The colourimetric method is affordable and portable. The limit of detection is lower right now, but it can be improved,” he said.

The team also investigated potential interference from a range of other metal contaminants and found that, with the exception of mercury, none of the metals interfered strongly, and even mercury only impacted the absorption spectrum slightly.

“This suggests that the sensor would be selective and not disturbed by other elements present in the drinking water,” Abbas explained. “In future, this method may lead to the design of a microfluidic device for detection of arsenic.”

Raman imaging microscopy: The analytical multi-tool

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Raman spectroscopic imaging is a powerful, versatile and increasingly common microscopy technique that can quickly identify molecules in a sample and visualize their distribution in three dimensions. This fast, nondestructive and label-free chemical characterization method offers enormous potential to physicists in many fields of research.

Modular Raman microscopes can be integrated with advanced cooling stages for cryogenic measurements, with environmental enclosures for remote operation, and even within vacuum chambers for advanced structural analyses.

This presentation will describe the principles of 3D Raman imaging and the speakers will show in detail how to access chemical imaging at the highest spatial resolution.

Comprehensive analyses of samples often require a combination of different techniques. Structural information on a sample’s surface can be obtained by Atomic Force Microscopy or Scanning Electron Microscopy (SEM). Raman imaging can reveal its chemical composition and by combining the techniques, structural and chemical information can be easily acquired from the same sample position. These approaches will be described and the power of correlative Raman-AFM and Raman-SEM imaging for analysis will be illustrated in the contexts of 2D materials development, cryogenic research, pharmaceutical sciences, geosciences, battery research and life sciences.

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Thomas Dieing is technical product manager for the WITec alpha300 product line and its accessories. He obtained his PhD from La Trobe University, Melbourne, Australia, in 2005 investigating the MBE growth of nitrogen containing III/V semiconductors. In 2006 he joined WITec’s application team and became director of applications and support. In his role as product manager since 2019 he is responsible for all activities related to the product development process.

Ute Schmidt studied physics at the Babes Bolyai University in Cluj-Napoca, Romania, and obtained her PhD from the University of Karlsruhe, Germany. Through her work with in situ scanning tunneling microscopy in an electrochemical environment, she was introduced to scanning probe microscopy. During her postdoctoral scholar position at Karlsruhe and North Carolina State University in Raleigh, USA, she continued to work with metal deposition on different substrates with STM and Atomic Force Microscopy. Schmidt worked for six years as a project manager at Molecular Imaging Corp., Phoenix, USA. She has been an applications manager at WITec since 2003.

Alan Turing £50 note is unveiled, how to get a mortgage on the Moon

The Bank of England has unveiled the final design of its new £50 polymer banknote that features the mathematician and wartime codebreaker Alan Turing. The new £50 – the last of the bank’s notes to go from paper to polymer – will come into circulation on 23 June, which is the 109th anniversary of Turing’s birth. “He was a leading mathematician, developmental biologist and a pioneer in the field of computer science,” says Bank of England governor Andrew Bailey. “He was also gay and was treated appallingly as a result. By placing him on our new polymer £50 banknote, we are celebrating his achievements, and the values he symbolizes.”

As with the other new polymer notes there are a series of security features such as holograms and foil patches to make them more difficult to forge. And to mark the occasion, the UK’s intelligence agency GCHQ has set the “Turing Challenge”, which consists of twelve puzzles that increase in complexity leading to one final answer. The agency says it is their toughest puzzle yet, but surely it can’t be as hard as cracking the Enigma code machine.

Turing was certainly a visionary in several scientific fields, but if he were around today would he invest in a house on the Moon? If you are interested in living in what would surely be an ultralow density development, all you need is a £4.4 million deposit to get on the lunar property ladder. That is the claim of the website Money.co.uk, which reckons that the first house on the Moon would sell for a little over £44 million. You can read more about this hypothetical housing development in “How to get a mortgage on the Moon!”.

Three top atomic clocks are compared with record accuracy

The time kept by three of the world’s best atomic clocks has been compared by connecting them using optical fibres and an over-air link. The comparisons were done by the Boulder Atomic Clock Optical Network Collaboration in the US and are ten times more accurate than previous attempts. The measurements have revealed unexpected variations in the time kept by the clocks, which could provide insights into how the devices could be improved. The research could play an important role in developing a new standard for the second, which would involve distributing and comparing atomic-clock time signals throughout the world.

Atomic clocks use the frequency of a specific atomic transition as an extremely stable time standard. While the second is currently defined by caesium-based clocks that operate at a microwave frequencies, physicists have built much more accurate clocks that are based on light. These optical clocks tick at much higher frequencies than microwave clocks and can keep time that is accurate to about one part in 10¹⁸, which is about 100 times better than the best caesium clocks.

The international metrology community aims to replace the microwave time standard with an optical clock, but first must choose from one of several clock designs being developed worldwide. To evaluate and improve these optical clocks – and ultimately create a global network of time standards – researchers must be able to compare their time signals. This can be done using an optical fibre connection or by transmitting optical signals through the air. Indeed, air transmission could play an important role in deploying optical clocks in satellites, where microwave clocks are currently used.

In this latest work, David Hume and colleagues at the US’s National Institute of Standards and Technology (NIST) and the University of Colorado have compared time signals of three optical clocks, which are all located in Boulder Colorado. One clock uses ytterbium atoms, another strontium atoms and the third a combination of aluminium and magnesium ions.

Frequency combs

A 3.6 km optical fibre link was used to compare the ratio of frequencies of the ytterbium and strontium clocks, which were located at NIST and the University of Colorado respectively. The strontium and aluminium–magnesium clocks (the latter located at NIST) were compared using a 1.5 km over-air optical link between two buildings. This involved the use of frequency combs, which allow signals at very different frequencies to be compared.

The over-air technique is also relatively immune to disturbances caused by turbulence in the air. Indeed, the team found that the fibre and free-space links offered similar levels of performance – the exception being when the free-space link was operated during a snowstorm.

The ytterbium and aluminium–magnesium clocks were in different labs at NIST and were compared using a fibre connection.

“State-of-the-art”

The team managed to measure ratios of frequencies of the three pairs of clocks at an accuracy of one part in 10¹⁸, which is an order of magnitude improvement on the previous record of one part in 10¹⁷. Hume describes the work as “state-of-the-art for both fibre-based and free-space measurements”. These ratios are natural constants, so the team points out that their results are the three most accurate measurements ever made of natural constants.

The clocks were compared over a period of several months and the researchers found unexpected day-to-day variations in their time keeping. This suggests that the team does not have a complete understanding of what affects the performance of the clocks – which means that further improvements could be possible.

As well as improving the definition of the second, better comparisons of optical clocks could benefit other branches of science. Two clocks at different elevations will run at slightly different rates and this could be used to measure tiny shifts in the Earth’s crust, caused for example by the melting of ice sheets or rising sea level. Differences between clocks could also be used to try to detect dark matter.

The measurements are described in Nature.

Hamish Johnston visited NIST in 2019 and spoke to David Hume and other atomic-clock experts. You can hear those conversations in this episode of the Physics World Weekly podcast.

Ultrafast low-dose PET scans will benefit cancer patients

Reduced radiation dose and shorter exam times for PET/CT scans are big advantages for cancer patients, who may require multiple scans during their treatment and who may find it challenging to remain motionless during a typical 20 min PET scan. Radiologists at the Wright Center of Innovation at Ohio State University Wexner Medical Center have managed to reduce PET scan duration to approximately 2 min, thereby reducing patient discomfort, minimizing motion artefacts and improving patient throughput.

At the recent European Congress of Radiology (ECR 2021), Michelle Knopp discussed the team’s latest beneficial innovation: lowering the ¹⁸F-FDG radiotracer dose from the standard-of-care (480 MBq) to the lowest amount allowable by product label (185 MBq). Results of a phase II prospective study of 105 cancer patients revealed that images acquired by an ultrafast 2 min PET/CT scan, using a 185 MBq radiotracer dose, are of diagnostic quality in patients with a body mass index (BMI) under 35.

The researchers performed ¹⁸F-FDG PET imaging 60–75 minutes post-injection using both conventional (90 s per bed position) and investigational (9 s per bed position) acquisitions. For the ultrafast acquisition, the researchers used an organ-, BMI-adaptive regularized reconstruction, which takes into account the bed location and the patient’s BMI. For the 90 s acquisitions, they employed standard EARL reconstruction techniques.

Two blinded readers independently performed visual and quantitative assessment for each data set. Knopp reported that for patients with a BMI under 35, both sets of images were of diagnostic quality. However, for patients with a BMI of 35 or greater, only eight (35%) of the ultrafast, low-dose exams were of diagnostic quality.

“Combining the third-dose with the ultrafast acquisition (9 s versus 90 s per bed position, for a total acquisition time of 2 min versus 20 min) represents an exam time that is one-tenth of the normal time,” explained Knopp. “This is a critical point for many patients, as faster imaging allows for less patient discomfort, leading to less motion artefacts. Additionally, faster acquisition opens the door to dynamic imaging of tracer uptake, which may help reveal additional clinical information about therapy response in cancer patients, and activity of infection in patients with infection.”

“Using these techniques, we are acquiring the source data at about one twentieth of the normal count density,” she added. “Previous reconstruction methodology was generating very noisy and blobby images. The adaptive regularized PET reconstruction approach has opened the door to EARL-equivalent diagnostic image quality.”

Knopp tells Physics World that based on the findings of the phase II study, new research will focus on 15 s per bed position (3 min total acquisition time) whole-body PET scans for patients with higher BMIs. She and her colleagues are currently conducting a phase III clinical trial to investigate this approach.

PET-based lymph node assessment

Surgical sampling of axillary lymph nodes in newly diagnosed breast cancer patients is essential to assess their nodal status and plan suitable treatment. But this procedure can cause discomfort and pain for the remainder of a survivor’s life. Being able to accurately determine nodal status with diagnostic imaging could eliminate unnecessary surgical sampling in node-negative patients.

At ECR 2021, Janna Morawitz, from the Institute of Diagnostic and Interventional Radiology at the University Hospital of Düsseldorf, presented the findings of a study comparing the use of four imaging modalities to assess nodal status. The multi-institute analysis revealed that thoracic ¹⁸F-FDG PET/MRI outperformed axillary sonography, breast MR and thoracic MRI in determining the axillary lymph node status of women with newly diagnosed invasive breast cancer.

The study included 44 patients with positive nodes and 68 with negative nodes, based on histopathological diagnosis. All patients underwent all four imaging exams. Thoracic PET/MRI exhibited both the highest accuracy (90.18%) and sensitivity (81.8%) of the four modalities, followed by axillary sonography, with an accuracy of 87.04% and a sensitivity of 69.1%.

Thoracic PET/MRI also had the highest negative predictive value, at 89.0%, followed by axial sonography at 83.3%. However, axillary sonography, the most commonly used imaging exam, had the highest specificity (98.5%).

Morawitz reported that eight patients with positive lymph nodes were missed by PET/MRI, but that these were also missed by the other three modalities. In total, axillary sonography generated 13 false negatives, followed by thoracic MRI (16) and breast MRI (17). Axillary sonography had the lowest number of false positives, with only one case, followed by thoracic MRI with two cases, and then breast MRI and thoracic PET/MRI with three each.

“In a clinical setting, the combination of PET/MRI and axillary sonography might be considered to provide even more safety in making a diagnosis and in reducing the number of unnecessary surgical samplings performed,” said Morawitz. “Radiologists could use PET/MRI as a searching tool because of its high sensitivity, and add axillary sonography afterwards to specific findings if suspicious lymph nodes are identified.”

Retraction of Nature paper puts Majorana research on a new path

A high-profile publication that claimed to have discovered the elusive Majorana quasiparticle has been retracted after a re-analysis found no such evidence. In 2018 Leo Kouwenhoven from the Delft University of Technology (TU Delft) and colleagues declared they had found the particle in an extremely thin semiconductor nanowire covered by a superconducting layer (Nature 556 74). Yet on 8 March Nature published a retraction after “inconsistencies” with the original analysis came to light. An independent report commissioned by TU Delft, however, found no instances of data fabrication.

The Majorana fermion, a particle that is its own antiparticle, is the brainchild of Italian theoretical physicist Ettore Majorana, who disappeared mysteriously in 1938 after boarding a ferry from Naples to Palermo. It is not a discrete particle but a quasiparticle and consists of two paired electrons. The pair exist in two energy states as well as in a superposition state, just like “qubits” that consist of electrons or photons.

How and where to search for the Majorana particle remained elusive until work in the 2010s by two research groups. Sankar Das Sarma and co-workers from the University of Maryland proposed looking for the Majorana in nanowires consisting of semiconductor-superconductor heterostructures (Phys. Rev. Lett. 105 077001). Then, in 2012 Kouwenhoven and his international team at the QuTech lab at TU Delft published a paper hinting at their existence in semiconductor-superconductor nanowires (Science 336 1003). Physics World picked the finding as one of its top 10 Breakthroughs of the Year.

If we do not deliver eye-popping breakthroughs, the entire research direction gets cancelled and we need to do something else
Sergey Frolov

Four years later, Microsoft set up the Microsoft Quantum Lab at TU Delft in 2016, with Kouwenhoven as its director. In 2018 he and his team published the paper in Nature claiming to have detected the Majorana quasiparticle in an extremely thin semiconductor nanowire covered by a superconducting layer. At a temperature of 0.02 K, they showed that two electrons paired up at the end of the wire with one electron in the semiconducting part and the other electron in the superconducting layer. However, the team could only prove the existence of one electron pair and not the existence of the second electron pair that together would have formed a Majorana qubit.

Several physicists, though, were unconvinced. Sergey Frolov at the University of Pittsburgh and Vincent Mourik at the University of New South Wales independently analysed the result, discovering “several inconsistencies” that led them to conclude there was no proof of a Majorana qubit. As a result of these criticisms, Kouwenhoven and co-workers re-analysed the raw data and rebuilt the experimental set-up to recalibrate certain parameters – finding that the results were inconsistent with a quantized Majorana conductance. “We apologize to the community for insufficient scientific rigour in our original manuscript,” the authors wrote in a retraction published on 8 March (Nature 10.1038/s41586-021-03373-x).

On the same day as the retraction, an independent report written by four physicists that was commissioned by TU Delft concluded there were no instances of data fabrication. “There was some degree of data selection in what was published,” says Patrick Lee from Massachusetts Institute of Technology, who was one of the authors of the report. “I don’t think this was done with malice. I think they were caught up at the excitement of the moment.” Lee notes that “some mistakes” were made by the team such as a calibration error, which they discovered after the publication of the paper. “They were aware of it and they came out with it without holding back anything,” says Lee. Indeed, Lee adds that he does not think that Microsoft is in trouble given its links to TU Delft. “It is a setback, but it should not derail the whole enterprise,” adds Lee.

Frolov says that quantum research is vulnerable to mistakes given it is complex science and that many teams are racing to build quantum computers. “We do not have the luxury of being supported to do the same thing for decades – we operate on 3- to 5-year grant-renewal cycles,” says Frolov. “And if we do not deliver eye-popping breakthroughs, the entire research direction gets cancelled and we need to do something else. This is the root cause of hype that we get criticized for.” Frolov adds that researchers will now have to look for different ways of creating Majorana qubits.

Theoretical physicist Michael Wimmer from TU Delft says that some in the field are now using “Majorana mode” for condensed-matter systems to distinguish it from the “fundamental” particle. “From a theoretical perspective, we know that it is possible to make Majorana modes in a suitable system – the theory behind it is well understood,” he says. “The question is whether such conditions were successfully achieved in an experiment so far.” Meanwhile, Das Sarma says that the retraction of the Delft paper “means little to the subject”. He is convinced that his group’s findings stand and says the ones from Delft will too. “The same experiment with better samples should show Majorana [particles],” he says.

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LATTICE radiotherapy plus immunotherapy shows promise for treating advanced bulky tumours

Carbon ion grid therapy spares healthy tissue

Strolling in the deep