Interventional News Issue 72—November 2018 US Edition

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Trauma embolization

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Kevin Mani:

Gerard Goh:

Profile

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Expanding horizons in critical limb ischaemia treatment may benefit “no option” patients Up to 40% of patients diagnosed with critical limb ischaemia (CLI) do not have positive clinical outcomes with the revascularisation treatments currently offered as standard practice, representing a “pressing, unmet clinical need” according to Sanjiv Sharma (All India Institute of Medical Sciences, New Delhi, India).

Cell-based therapies are the future of CLI management

“If you can have a drug-eluting stent, why not have a stem cell-eluting stent?” Sharma asked the CIRSE audience (see page 6). Sharma argued that a paradigm shift in the management of CLI is on the horizon, insisting that he has “little doubt” cell-based therapies will change the way clinical medicine is practiced in the years to come.

Sharma explained: “Many times, a strategy for surgical or endovascular revascularisation may not be feasible due to anatomically irreparable disease. Hence, management strategies are constantly evolving. New endovascular techniques and devices may improve short-term outcomes but fail progressively with time and eventually are not much better than conventional techniques at long term, despite major treatment cost escalation.

“We have a biological problem, and we are trying to find a mechanical solution to solve this. To my mind, this is the fundamental flaw in the management of CLI. Angiogenesis and cell-based therapies have emerged as a new frontier in this treatment and have the potential to fulfil a crucial clinical need.”

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Interventional radiology societies call for expanded stroke training In a joint, global position statement, the Society of Interventional Radiology (SIR), Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and the Interventional Radiology Society of Australasia (IRSA) have committed to providing necessary stroke training to interventional radiologists in order to alleviate the shortage of physicians trained in endovascular stroke therapies.

S

peaking at the 34th annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22¬25 September, Lisbon, Portugal), Sharma, Jim Reekers (University of Amsterdam, Amsterdam, The Netherlands), and Roberto Gandini (Policlinico Tor Vergata, Rome, Italy) looked ahead to the future of CLI management, focusing on emerging therapies that will transform today’s standard of care, and that will target these “no option” patients.

Radiation protection

Stem cell therapies exploit the natural, reparative mechanisms of the human body. When vasculature is damaged, stem cells situated in remote locations of the body migrate to the site of injury and stimulate arteriogenesis and capillary sprouting. However, for CLI patients, the disease progression results in endothelial dysfunction and chronic inflammation, which mitigates the positive impact the stem cells would otherwise have. The concept underpinning stem cell therapy is that by adding exogenous growth factors to encourage stem cell migration, more arteriogenesis occurs.

Despite the improved arteriogenesis, the method has several limitations. As the growth factors are recombinant proteins, they have a short half-life, poor biostability, and rapidly diffuse into the tissue surrounding the site of infusion.

These factors combined mean that physicians often use a supraphysiological dose, which has unpredictable outcomes – multiple injections may lead to excessive, uncontrolled vascular formation in undesired locations.

To date, there have been a lot of preclinical studies investigating the use of gene therapy. These phase I and phase II clinical trials clearly establish the safety of the treatment; no acceleration of retinopathy or atherosclerosis, Continued on page 4

THE ABILITY FOR patients to access thrombectomy-capable stroke centres remains stymied by geography and a shortage of interventional physicians, despite the American Heart Association’s and multiple international stroke organisations’ recommendations that endovascular thrombectomy (EVT or clot removal) be the standard of care for patients suffering acute ischaemic stroke caused by blocked arteries.

“The shortage of physicians and comprehensive stroke centres providing EVT has been confirmed by the stroke neurology community, who recommend that patients be treated locally rather than having long transfer delays,” the joint statement said. “Appropriately trained interventional radiologists can evaluate stroke patients and provide emergent EVT with good outcomes; especially where neurointerventional physicians are not available.” Interventional radiologists can also help provide 24/7 care in partnership with neurointerventional physicians where they are available, the statement said.

Endovascular thrombectomy is proven to save lives and improve outcomes for patients suffering acute ischaemic strokes. Patients who undergo these clot-removing treatments not only survive in greater numbers, but also have fewer resulting disabilities Continued on page 2

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Stroke

Interventional radiology societies call for expanded stroke training Continued from page 1

and are able to recover functions faster than best medical therapy.

“Reversing symptoms from these strokes requires rapid and safe removal of the occluding thrombus,” the societies said in the statement. Allowing interventional radiologists to join their neurology, neurointerventional and neurosurgeon colleagues on care teams and allowing them to be part of certified stroke centres will greatly increase access to this critical treatment, they said.

SIR is already revising its current stroke training guidelines to support expanded patient access to interventional stroke treatment. The training pathway will reinforce Joint Commission and American Heart Association requirements for physicians operating in thrombectomy-capable stroke centres and comprehensive stroke centres. In September, the Joint Commission and American Heart Association announced they would hold a dialogue with provider organisations to discuss requirements as the organisations work to update certification criteria for both thrombectomy-capable and comprehensive stroke centres.

Back in February 2018, the Joint Commission announced revised eligibility requirements for the Thrombectomy-Capable Stroke Centre (TSC) certification program. The revised eligibility included a requirement for all primary neuro-interventionists (i.e., those who routinely take call to perform emergency mechanical thrombectomy) to either be certified by the Committee for Advanced Subspecialty Training (CAST) or to meet similar criteria, including education, training, and experience performing 15 mechanical thrombectomies over the past 12 months or 30 over the past 24 months. In the May 2018 edition of Perspectives, the Joint Commission announced that this same requirement would be applied to Comprehensive Stroke Centres.

Since the publication of these revised eligibility criteria, a number of individuals and organisations have raised concerns about the individual physician training requirement for CAST certification or the equivalent. First, many expressed that the requirement is overly stringent and is not necessary to ensure that patients at TSCs and CSCs receive high quality mechanical thrombectomy because CAST certification requires training and ongoing experience in a number of procedures other than mechanical thrombectomy (e.g., interventions for aneurysms and arteriovenous malformations).

Second, the training requirement excludes many highly qualified individuals, i.e., interventional radiologists who have training and experience in neurovascular interventions and have been performing mechanical thrombectomy successfully for years. The

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Joint Commission originally thought these individuals could become CAST certified through the Practice Pathway; however, this is not possible for them because they are not doing other neuroendovascular procedures required for individual CAST certification.

SIR president M Victoria Marx, an interventional radiologist at Keck Medicine of the University of Southern California, USA, said, “SIR strongly believes that interventional radiologists have a current and growing role in the care of patients with ischaemic strokes. We stand committed to advocate for policy changes and provide the cognitive and technical skills and resources necessary for interventional radiologists to provide high-quality care.”

Thirdly, limiting eligibility with these requirements could adversely affect access to mechanical

SIR strongly believes that interventional radiologists have a current and growing role in the care of patients with ischaemic strokes. thrombectomy. One healthcare system said they had no physician in their system that met the training requirement. The system provided data showing that the clinical outcomes for their eight interventional radiologists were similar to those reported in clinical trials; all of the physicians had neuroendovascular procedure training in an accredited program, but none had completed a neuroradiology fellowship. In addition, the Society of Interventional Radiology sponsored an independent analysis of which specialties were performing mechanical thrombectomies for Medicare patients. Of the 5,914 claims, 37% were performed by physicians who identified themselves as diagnostic radiologists, 27% by neurosurgeons, 20% by neurologists, and 16% by interventional radiologists.

Concerns have also been raised pertaining to the individual physician volume requirement of 15 mechanical thrombectomies over the past 12 months or 30 over the past 24 months, adopted by the Joint Commission based on CAST requirements. Analyses conducted by one healthcare system showed that only three of the eight interventional radiologists in their

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system were at or near this benchmark. The CAST volume requirement was adopted by the Technical Advisory Panel of the Joint Commission because it was a concrete benchmark used by a national organisation.

However, the panel acknowledged that there were no adequately powered studies available to determine a distinct threshold for a volume-outcome relationship.

In addition, SIR sponsored an independent analysis of the 2016 Centers for Medicare and Medicaid Services (CMS) Physician Supplier and Provider Services (PSPS) files and Provider Utilization File (PUF). Of the 995 physicians who billed under code 61645 (percutaneous arterial transluminal mechanical thrombectomy and/or infusion for thrombolysis, intracranial, any method, including diagnostic angiography, fluoroscopic guidance, catheter placement, and intraprocedural pharmacological thrombolytic injections), 842 (85%) billed for 10 or fewer procedures. For the 153 (15%) physicians who performed more than ten procedures, the median number of procedures was still only 15. This analysis is limited because it does not include procedures billed to private insurers, the procedures under the target billing code are heterogeneous, and the data are from 2016 when the indications for mechanical thrombectomy were more restrictive than current ones.

Despite these limitations, the data raise important questions about whether the current individual physician volume requirements for the TSC and CSC certification programmes would exclude too many qualified individuals. the Joint Commission and the American Heart Association believe that additional dialogue is needed with national stakeholder organisations to discuss individual physician training and volume requirements.

For these reasons, the Joint Commission removed the individual physician training and procedure volume requirements for both the TSC and CSC certification programmes, in September 2018. The facility volume requirement of 15 mechanical thrombectomies per year will still be in force for both certification programmes, however. In an Autumn statement, the Joint Commission said: “We hope to establish new, more appropriate individual physician requirements within the next six months.”

Stroke affects 16.9 million worldwide each year, with 795,000 new cases in the USA annually.

Approximately 100,000 of the US cases are eligible for EVT treatment, yet only a fraction are treated due to the shortage of thrombectomy-capable stroke centres. To meet that volume, the USA would need 500 endovascular stroke centres and 2,000 physicians. It currently has 231 thrombectomycapable stroke centres.

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Critical limb ischaemia

Expanding horizons in critical limb ischaemia treatment may benefit “no option” patients Continued from page 1

and no cancers or mortalities have ever been attributed to the use of plasmid and viral vectors in the literature, and several thousand patients have now been treated with this therapy.

Much research today is dedicated to the identification of potential scaffolds that would make the exogenous growth factors more stable, and force them to stay at the disease site long enough to have a clinical impact. “This is where gene-eluting stents may have a role to play in the future.

But unfortunately, much of the clinical work based on gene therapy today is still in the realm of fantasy,” Sharma informed delegates.

However, current work does exist which evidences the success of stem cell therapy in the treatment of CLI. Stem cells have three basic properties which make them ideally suited to this: plasticity, homing, and engraftment. Moreover, stem cells are autologous, there are no side-effects, and there is no carrier required due to their stability.

Translating basic research into a clinical setting can often be challenging, but cell-based therapies have proven their

can predict with almost 100% certainty if a patient will have an amputation in the next year.” This knowledge can then be applied clinically to prevent unnecessary reinterventions in patients where secondary percutaneous transluminal angioplasties (PTAs) are likely to fail.

The method devised by Reekers and colleagues exploits the fact that a dysfunctional sympathetic nervous system corresponds to higher amputation rates, a correlation previously evidenced in the medical literature. This is because if the peripheral nervous system does not function, communication between the nervous system and alpha receptors on the arterioles is disrupted. This communication channel usually allows the peripheral nervous system to control the arterioles through autoregulation processes, resulting in peripheral resistance and ultimately limiting blood flow from the feeding arteries to the capillary bed, via the arterioles. In the absence of arteriole control, peripheral resistance decreases, and, according to Reekers, the “microcirculation explodes” in the capillary bed as the blood pressure surges. Higher blood pressure damages the

We can now identify in which patients a reintervention will probably be in vain. This is a major step forward in patient management. safety and at least variable efficacy in several preclinical and small clinical studies. Indeed, Sharma points to recent promising trials investigating the use of stem cell therapy in the treatment of CLI. In the first in-human, double blind, randomised, placebocontrolled trial, which Sharma and colleagues completed recently, 92.6% of the 40 patients in the treatment arm benefitted from the experimental therapy. The control group received an optimised medical therapy, followed by a sham injection, while the treatment group received the same optimised medical therapy, followed by an injection of 60–100 million autologous, bone marrow derived stem cells. There was a 0% amputation rate in patients with nohope, no-option CLI in the treatment arm, and a statistically significant improvement in pain-free walking distance was observed in 92.7% of patients in the intervention arm.

Additionally, there were no procedure related complications or 30-day mortality.

The future of stem cell therapy in the treatment of CLI will be even more impressive, Sharma argued, as the cells utilised in today’s trials are not the most efficacious, and the doses used may well prove to be sub-optimal. Despite these limitations, the results are already encouraging. “The important fact is: this treatment method does deliver,” Sharma stated.

Interventional radiologists will be able to forecast amputation rates in diabetic CLI patients “with almost 100% accuracy”

“I think we have to start with re-thinking our whole concept of CLI,” Reekers told delegates at the CIRSE 2018 annual meeting. As an interventional radiologist at the frontier of CLI research, Reekers presented a novel, highly accurate method of predicting which diabetic CLI patients will require amputation following successful revascularisation.

For more than 30% of diabetic CLI patients with neuroischaemic ulcers, a technically successful revascularisation resulting in foot improvement and increased foot perfusion does not always mean a clinically successful outcome; the amputation rate is still very high, with more than 30% of these patients being amputated within 12 months of treatment.

Reekers’ research demonstrates a way of forecasting which patients will need amputations. He told the CIRSE audience: “The most striking finding [of this research] is that if you have a non-functioning sympathetic nervous system – which can be easily tested in five minutes – you

thin capillary walls, with leakages and hyaline deposits causing a thickening of the capillary basement membrane.

This thickening in turn blocks the diffusion of oxygen from the blood to the surrounding tissues; hence, sympathectolysis leads to flow independent critical limb ischaemia which cannot be treated by revascularisation procedures and therefore often necessitates amputation.

As it is hugely difficult to test the peripheral nervous system directly, the study investigators utilised perfusion angiography as an imaging tool to indirectly determine nerve functioning. Thirty-one patients, all diabetics, were given the alpha blocker Tolazoline to locally block the alpha receptors on the arterioles and to mimic the effects of peripheral nervous system dysfunction in the foot. Using perfusion angiography, the investigators were able to measure total flow. As the majority of blood flow in the foot (>80%) is through microcirculation, this calculation allowed the investigators to determine if peripheral resistance was decreased in this cohort, and thus served as a proxy for parasympathetic nervous system functionality.

Of the 31 patients, 11 did not respond to the alpha blocker, indicating dysfunctional autoregulation. Notably, all 11 had an amputation within 12 months of revascularisation treatment. In contrast, only three of the remaining 20 patients (all of which did react to the alpha blockers) underwent amputation. Of these results, Reekers commented, “This technique has demonstrated that it has a very high predictive value for amputation in diabetic patients if they have a nonfunctioning nervous system.”

According to the abstract of Reekers’ presentation, perfusion angiography is the only modality that is able to measure total organ flow including that of macrovessels, microcirculation and tissue, and flow distribution.

Reekers says that the technique “can be used to measure the difference in local flow as well as flow changes after intervention. It has the potential to be used for functioning imaging after pharmacologic interventions measuring the flow changes.” Perfusion angiography alone cannot quantify flow measurements, so is used in conjunction with a software application from Philips Healthcare. Reekers et al used the perfusion angiography flow volume changes before and after the administration of Tolazoline to calculate an objective measure of sympathetic nervous system function called the capillary resistance index (CCI); a normally functioning sympathetic nervous system is indicated by a CCI below 0.9. The eleven patients that did not respond to

the alpha blocker all had a CCI above 0.9.

“Testing the sympathetic nervous system of the foot with perfusion angiography has a very high predictive value for early amputation in diabetic patients with a neuro-ischaemic ulcer or other foot problems,” Reekers summarises.

Commenting on the clinical implications of this conclusion, Reekers continues, “If there is no ulcer healing after successful revascularisation in a patient with a nonfunctional sympathetic nervous system, then a second reintervention is probably useless. So now we can stop going in and doing re-PTA and implanting a stent, because we know that in these patients – making up 30% of our cases – we can identify that a re-intervention is probably going to be in vain. I think this is going to be a major step forward in the management of our patients.

“This is the way we should go forward: predicting the clinical outcome prior to intervention, and then selecting our patients appropriately.”

Novel drug delivery technologies

Ultrasound plasty and atherectomy devices are the future of drug delivery systems, Gandini believes. Recent research has shown that a combination of ultrasound plasty and atherectomy devices demonstrate improved outcomes when used in combination with drug-eluting approaches.

Ultrasound plasty modifies the plaque structure, theoretically allowing a more efficacious penetration of drugs. Using the same approach, atherectomy, coupled with the ablation of atherosclerotic calcific plaque, enables an increased effect of the drug on vessel wall.

Gandini writes that the “advent of drug-eluting devices and other technologies, such as cutting balloons, atherectomy, and cryoplasty, is a direct result of wanting to decrease restenosis rates arising from endovascular interventions for CLI.” Two different drugs have been used in drug-eluting stent and balloons: paclitaxel, an antineoplastic drug; and sirolimus (and sirolimus analogs such as zotarolimus and everolimus), an immunosuppressant. Both drugs are lipophilic, which enhances tissue uptake; however, determining and efficiently delivering an optimal dose remains a challenge. Drug densities used on drug-eluting balloons are generally higher than those used on drug-eluting stents because the amount of time available for drug transfer is significantly less with balloon inflation than it is with stent implantation.

Drug-coated stents and drug-coated balloons have been the focus of technological innovation in preventing and treating restenosis, Gandini informed the CIRSE delegates. In the last five years, six meta-analyses have synthesised data from many recent clinical trials to examine the efficacy of drug-eluting technologies compared with conventional approach.

Despite the introduction of these new technologies, drug-eluting trials report a 10% to 20% rate of restenosis that persists in patients with claudication, and according to Gandini there has been little focus on severely calcified and long lesions, where results with other treatment modalities have been associated with worse clinical outcomes and higher rates of restenosis. In particular, calcified lesions should reduce the effect of drug-eluting technologies, jeopardising the penetration of drugs into the vessel wall.

Therefore, ultrasound plasty and atherectomy devices are the way forward, Gandini argued. “The idea is to improve drug efficacy through an ablation or modification of the plaque,” he explained. “Another concept is to modify the consistency, or the permeability of the arterial wall using ultrasound. This would improve drug passage through the vessel wall. It is well demonstrated that a lower frequency of ultrasound [20kHz] changes calcific plaque compliance, and significantly reduces balloon dilatation pressure during angioplasty.”

Further studies are needed to confirm the efficacy, but Gandini hypothesises that the use of drug-eluting balloons in association with ultrasound plasty could improve outcomes in CLI patients.

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Stem cell therapy is the future of critical limb ischaemia management Sanjiv Sharma Comment & Analysis Addressing the audience at the 34th annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September, Lisbon, Portugal), Sanjiv Sharma asks: “If you can have a drug-eluting stent, why can’t you have a stem cell-eluting stent?” Here, Sharma argues that a paradigm shift in the management of critical limb ischaemia is on the horizon, with stem cell therapies proving safe, effective, and less costly than surgical or endovascular revascularisation.

M

anagement strategies for critical limb ischaemia (CLI) are constantly evolving due to issues and challenges with the image morphologies in below-the-knee vessels and rapidly changing device technologies, mostly with unmet longterm outcome expectations. Many times, a strategy for surgical or endovascular revascularisation may not be feasible due to an anatomically irreparable disease. New endovascular techniques and devices may improve short-term outcomes but fail progressively with time, and eventually are not much better than conventional techniques over the long term, despite major cost escalation.

Therapeutic angiogenesis using cell based (stem cell) therapies has emerged as a new frontier in this treatment and has the potential to rewrite the treatment algorithms in patients with critical or chronic limb ischaemia.1–3

Stem cell characteristics

These stem cells have three characteristic properties that make them well suited for this treatment: plasticity, homing and engraftment. Stem cells derived from early human embryos are pluri-potent and can generate all committed cell types. These generated cells are higher in number, and have better expansion potential and differentiation abilities when compared with stem cells from adult tissues, but have issues related to adverse effects and ethical concerns.

Hence, the clinical experiences are largely restricted to the use of autologous adult stem cells in various disease states.

The migration, differentiation and growth of stem cells are mediated by the nature of the tissue, degree of injury and the type of stem cells involved. Damaged tissue releases factors that induce homing of these cells to the site of injury.

In ischaemic tissues, endogenous

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biochemical agents are released, stimulating angiogenesis. The angiogenesis is developed by vascular cell proliferation and new capillary formation. Pre-clinical studies have shown that angiogenic growth factors promote the development of collateral arteries, a process that is termed therapeutic angiogenesis. This angiogenesis can be achieved either by growth factors or genes encoding these proteins. Endothelial progenitor cells in the CD34+ stem cell fraction of

outcomes, and the role of adjunct therapies in potentiating the effects of cell-based therapies.

Stem cell treatment proven safe and effective in “no option” patients

We conducted a pilot project using graded doses of stem cells in a group of patients with CLI and showed that a benefit, in terms of relief of rest pain and healing of ischaemic ulcers, was seen in all patients in the treatment arm.

This benefit was not dependent on the dose of injected stem cells beyond a threshold dose. Whereas in the control arm, no improvement was seen in any patient; CLI improved in all patients in the treatment group who received three graded doses of stem cells. No adverse effects related to the treatment were seen in any patient.

Subsequently, we conducted a randomised first in-human placebo controlled double blind clinical trial that included 80 patients with no option CLI not suited for any form of revascularisation. There was a 1:1 randomisation in control and treatment arms, and the patients were followed for at least six months after this treatment.

All patients received an injection, either of stem cells, or a sham injection indistinguishable from the stem cells.

Both the operator and the physician who evaluated the patients during follow-up were blinded to the mode of therapy.

This trial was recently concluded and the results have established the safety and efficacy of autologous stem cell therapy for limb salvage in these patients.

Evidence of therapeutic angiogenesis as evidenced by a demonstrable increase in collateral density after stem cell therapy and 0% amputation rates in the treatment

The therapeutic potential of stem cells may be enhanced by combining this treatment with gene therapy. adult human peripheral blood and bone marrow cells also take part in postnatal neo-vascularisation after mobilisation from bone marrow, and contribute to this angiogenesis.

Stem cells can be extracted from various sites, including the bone marrow, peripheral blood and adipose tissue.

These can be administered to the affected area by intra-arterial or intra-muscular delivery. Both these routes of delivery have shown clinical benefit in multiple studies.4–6 Preclinical studies have proven the safety of this treatment method and a variable efficacy in terms of relief of induced ischaemia. Current research revolves around establishing the most suitable source of autologous stem cells, the optimal route of delivery, the right dose of cells, as well as the role of single versus multiple injections for the desired clinical outcomes, the optimal method for assessment of clinical and imaging

arm was observed.

There is some evidence to suggest that the effect of this therapy may be more pronounced in Berger’s disease than in atherosclerosis.4 The barriers to the development of stem cell therapy relate to the autologous cell population that is often heterogeneous and may lead to varied responses. Also, to obtain the large cell numbers needed for transplantation, ex vivo cell expansion may be required, which leads to regulatory concerns and increased cost and time. Advanced disease also has the problem of cytokine resistance. Furthermore, the cell engraftment efficiency is typically low upon transplantation and may require multiple injections.

The potential of gene therapy The therapeutic potential of stem cells may be enhanced by combining this treatment with gene therapy. This

is likely to overcome insufficient paracrine release, poor cell survival upon engraftment, and lack of cell homing by controlling cell behaviour at the intracellular signalling level.7 To reduce the occurrence of in-stent restenosis, stents have been reshaped and improved in many aspects with the development of drug- and growth-factor eluting stents. Stem cells as a source of seeding cells for coating the stents have also been reported.8 In a recent study, mesenchymal stem cells derived from the bone marrow of New Zealand white rabbits were used as seeding cells and the authors observed that intimal hyperplasia and in-stent restenosis were significantly inhibited by the mesenchymal stem cell coated stent.

Although proof from large randomised trials for the above therapies is still inconsistent, these treatments have shown the ability to improve perfusion in selected patients. We have established the safety and efficacy of autologous stem cells in the treatment of “no-option patients” with critical limb ischaemia. Pre-clinical studies utilising a combination of cell and gene therapy have also shown encouraging results.

This may be an alternative option to address the limited number and function of progenitor cells in elderly patients, those with co-morbidities, and the challenge of cytokine resistance. Further research will define their role in suitable patients. The evidence for cell-based therapies is encouraging. There is a need for optimised trials to define the treatment algorithms in these patients.

Sanjiv Sharma is professor and head of the Department of Cardiovascular Radiology and Endovascular Interventions at the All India Institute of Medical Sciences, New Delhi, India.

References: 1. Chochola M, Pytlik R, Kobylka P, Skalicka L, Kideryova L, Beran S, et al. Autologous intraarterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia. Int Angiol.

2008;27(4):281-90.

2. Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M, et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. Am Heart J. 2008;156(5):1010-8.

3. Amann B, Luedemann C, Ratei R, Schmidt-Lucke JA. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant.

2009;18(3):371-80.

4. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease metaanalysis and systematic review of the literature.

Atherosclerosis. 2010;209(1):10-7.

5. Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res. 2017;120(8):1326-40.

6. Bura A, Planat-Benard V, Bourin P, Silvestre JS, Gross F, Grolleau JL, et al. Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy. 2014;16(2):24557.

7. Makarevich P, Rubina Rubina KA, Diykanov Diykanov DT, Tkachuk Tkachuk VA, Parfyonova Parfyonova YV. Therapeutic Angiogenesis Using Growth Factors: Current State and Prospects for Development. Vol. 9_2015. 2015. 59 p.

8. Bompais H, Chagraoui J, Canron X, Crisan M, Liu XH, Anjo A, et al. Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood. 2004 Apr 1;103(7):2577–84.

9. Wu X, Zhao Y, Tang C, Yin T, Du R, Tian J, et al.

Re-Endothelialization Study on Endovascular Stents Seeded by Endothelial Cells through Up- or Downregulation of VEGF. ACS Appl Mater Interfaces.

2016 Mar 23;8(11):7578–89.

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Interventional radiologists’ expertise essential in trauma embolization Miguel Angel de Gregorio Comment & Analysis With traumatic injuries caused by traffic accidents on the rise, Miguel Angel de Gregorio provides an overview of interventional radiologists’ role in performing embolization procedures to help the increasing number of trauma patients. De Gregorio also summarises the work presented at the Cardiovascular and Interventional Radiological Society of Europe 2018 meeting (CIRSE; 22–25 September, Lisbon, Portugal) on the Embolization for Trauma panel.

DESPITE PREVENTATIVE measures, no one can doubt that many technological advances have brought a considerable increase in the incidence of serious accidents that manifest themselves in incapacitating and even fatal injuries.

This increase in accident rates is closely linked to traffic accidents. According to the National Transportation Society Board (NTBS), in the year 2016 in the USA, more than 40,000 deaths were due to traffic accidents—involving a mean

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of 12.4 people per 100,000 inhabitants.

The measures of prevention and control of road safety, together with an improvement in the social conscience of drivers and workers, should reduce the rate of any type of accidents as well as their mortality.

Life support measures, coupled with emergency surgery, play an important role in the management of injured patients who arrive at hospitals. Through embolization procedures, interventional

radiology can contribute to the good management and stabilisation of these serious patients in a simple and safe way.

The CIRSE 2018 (Cardiovascular Interventional Radiological Society of Europe) Congress held on 22–15 September in Lisbon, Portugal, included the presentation and discussion of several papers covering trauma and vascular embolization.

Sanja Stojanović and myself moderated the session Embolization for Trauma, in which Christian ScheuringMeunkler (Berlin, Germany), Michele Citone (Florence, Italy), Dimitrios Karnabatidis (Patras, Greece) and Gary Siskin (Albany, USA) discussed the management of trauma of the spleen, liver, pelvis, and kidney, respectively.

In general, after life support measures, radiological imaging plays an important role in the diagnosis and extension of patients’ trauma. Computed tomography (CT) is the most important imaging technique, enabling a simple, safe and rapid way for the diagnosis of affected organs, as well as for detecting the presence of active bleeding. The image data and clinical assessment establishes the severity of the trauma and also helps to classify the trauma.

The World Society of Emergency Surgery (WSES) assesses four types of closed or open traumas depending on the intensity of the trauma and the anatomical lesions observed. The Organ Injury Scaling Committee for the American Association for the Surgery of Trauma (AAST) divides the type of lesions according to the degree of anatomical lesion (IV grades). Patients with severe trauma—WSES type IV and an AAST grade of AAST (ranging from

I–V)—and haemodynamic instability require surgical management (operative management), while in other degrees and levels, haemodynamic stability can be managed without surgery; this is non-operative management. In these latter types, patients are graded as WSES type I–II trauma. If angioCT and, most importantly, angiography establish vascular injury, embolization should be considered the treatment of choice.

There are many types of embolization agents, such as: absorbent gelatins, particles, gel foam, glues, coils, plugs alone or in combination. Embolization requires expertise, and interventional radiologists need to carefully decide which technique to use, such as distal, proximal embolization or combined, depending on the type of injury and the vascular anatomy of the organ or structure to be treated. Clinical results depend on the type of injury and the affected organ with few complications if the technique is adequate.

Endovascular techniques play an increasingly important role in the management of open and closed traumas with extensive vascular bleeding and injury; either to stabilise the patient, or to solve the problem.

Hybrid operating rooms near hospital emergency centres can improve the results by reducing intervention times, as well as allowing surgery before, during, or after embolization without mobilising the patient.

Miguel Angel de Gregorio is a professor at the University of Zaragoza, Zaragoza, Spain, and a member of the Minimally Invasive Techniques Research Group (GITMI), Government of Aragon, Spain.

Real-time imaging: Ultrasound detects a biodegradable embolic microsphere after prostatic artery embolization Researchers report the use of ultrasound to detect embolization in real time for patients undergoing treatment for benign prostatic hyperplasia (BPH). Richard Owen (University of Alberta, Edmonton, Canada) presented these results at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting (22–25 September, Lisbon, Portugal), demonstrating the clear visibility of the embolic agent Occlusin 500 Embolization Microsphere (OCL 503) within 24 hours of the prostatic artery embolization (PAE) procedure.

T

he study investigators set out to evaluate the safety and effectiveness of the embolic product OCL 503 in PAE for the treatment of men with BPH. The trial was small; 10 patients with moderate to severe lower urinary tract symptoms secondary to BPH were treated in this open label, single centre pilot study. A standard embolization technique in PAE was used: bilateral embolization using a 2.8F microcatheter. “A 2.8F microcatheter was required, because the embolic product is not compressible, and does not pass through a smaller microcatheter,” Owen said of this choice. The catheter position was confirmed with a cone beam CT at the time of the procedure.

Patients were imaged using a Philips Model IU22 ultrasound imaging system with a transabdominal approach before the procedure, within 24 hours of PAE, and at three months’ follow up.

Owen commented: “These particles [the embolic agents] are clearly visible in all of these patients, in the prostatic tissue, within 24 hours of embolization.

A blinded observation of the ultrasound images was able to identify patients that had a bilateral or

Richard Owen

unilateral embolization by the presence of these particles. Qualitative assessment of the signal intensity within 24 hours of PAE correlated with the number of microspheres delivered to the prostatic

tissue. As part of this study, we knew how many microspheres we delivered, and we knew in which patients ,of course. Within three months, none of the particles were visible.

“I am not sure what the clinical role will be, but it [the embolic agent] is clearly visible in the embolized prostate, and it is in fact visible in other tissues,” Owen continued. “I am not at liberty to discuss this here, but it is visible in other embolized tissues, as you would expect. That relates to the density; the density is higher than that of normal soft tissue, and that is why you get such a profound reflection from ultrasound.”

According to the study investigators, the echogenicity relates to the amount of embolic delivered. Owen explained at CIRSE: “It [ultrasound imaging] may well provide a useful tool at the time of embolization to confirm the entirety of embolization.

We used to use some other measures post-procedure, CT, for example, in post-procedure imaging, to see where the emboli are, but we could do a real time ultrasound here to see if we have reached an adequate endpoint—but it would require more work.”

Continued on page 9

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Continued from page 8

Embolization

Owen concluded his talk by expressing his gratitude to his mentor: “I did visit Portugal several years ago, and I learnt this technique from professor Martin Pisco (Hospital Saint Louis, Lisbon, Portugal), so thanks to him for starting the ball rolling in much of the world.”

A CIRSE attendee asked Owen if he had any experience with contrast enhanced ultrasound, which the questioner claimed to find “extremely useful” in the immediate monitoring of embolization. Owen replied: “You can do that, of course, although it requires the addition of a different agent; the intravenous injection of a contrast.

However, there could be other factors, for example spasm in the vessel, that might affect that endpoint [immediate imaging of emboli]. The use of OCL 503 and ultrasound imaging is not affected by those endpoints; it would reflect the actual embolic material in the tissue.”

The embolic agent

OCL 503 is a biodegradable microsphere, comprised largely of poly (lactic-co-glycolic acid) or PLGA, a bioresorbable suture material. It is a Class II medical device approved by the US FDA for use in hypervascular tumours, and is currently pending CE mark approval, as well as clearance for use in Canada. Owen described the microsphere: “It comes as a dry powder, similar to other embolics, and it is reconstituted with contrast—Isobuoyant with Omnipaque 240 in this case.” OCL 503 is eliminated from the body in three to six months, as has been evidenced in a previous animal study published in Cardiovascular and Interventional Radiology. The microspheres degrade to carbon dioxide and water, and have a density of 1.1g/ ml (in comparison to the 1.03g/ml of liver tissue, and 1g/ml of water).

9

Ultrasound imaging may well provide a useful tool at the time of embolization to confirm the entirety of embolization.

This research forms part of an ongoing trial investigating the OCL 500 series in PAE and uterine artery embolization, sponsored by IMBiotechnologies.

Owen is also a recipient of the Alberta Innovative Grant, and is a part-time consultant for Cook Medical.

New resorbable embolic agent for uterine fibroid embolization is effective A new, spherical resorbable gelatine embolic agent, GelBead, has been shown to be “very effective” for uterine fibroid embolization (UFE). Nigel Hacking (Department of Clinical Radiology, University Hospitals Southampton, Southampton, UK) presented this result at the 2018 annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September, Lisbon, Portugal).

THIS EMBOLIC AGENT is already available in the USA under the name GelBead (Vascular Solutions/ Teleflex; distributed by Medtronic), and is due for commercial release in Europe soon, where it will be called Optisphere.

GelBead is a purified porcine skin derivative (Hacking noted: “Interestingly, gelatine sponge and even trisacryl microspheres come from pigs. Gelatine products have been used for decades”), and has good mechanical strength.

Hacking detailed the embolic agent to the CIRSE audience, saying, “This product does degrade, unlike most of the polymer or plastic embolic agents, in around four to nine weeks, and in animal studies it had completely gone at 12 weeks.

“Those of you who have young children will know that plastics are bad, microplastics are worse, and this is one of the first non-plastic or polymer agents we have used. Not to say that the plastics cause any trouble—I do not think they do—but it is interesting that we may be moving towards resorbable agents in the future.”

Hacking and colleagues first conducted a pilot study, before enrolling a larger scale study evaluating GelBead in UFE in comparison with five established and commonly used embolic agents. GelBead compared very favourably to the existing agents. Those also under investigation for comparative purposes were: Gelfoam slurry (Spongostan Special: J&J Medical), trisacryl gelatine microspheres (Embospheres, Merit Medical), Beadblock

(Biocompatibles), Embozenes (Celonova), and particulate PVA (Contour, Boston Scientific).

Twenty-five women with symptomatic fibroids participated in the study, and all had a gynaecological assessment prior to treatment. The investigators took an MRI at baseline, and again three months’ postprocedure, to assess uterine size, number and position of fibroids, and size of dominant fibroid. Concerning the decision to have a three-month follow-up period, Hacking explains, “We know that threemonth MRI predicts beautifully what will happen in the future. You will get good symptomatic improvement. If you can kill all the fibroids, they will not come back.

If you only kill some of them, they will come back. So you do not need more than three months.”

Describing the assessment criteria of the study, Hacking said that he and his team did “something that is not all that common in these [types of] trials; we wanted to look at ovarian function, and whether this resorbable agent was more gentle on the ovaries, perhaps. So we looked at the anti-mullerian hormone (AMH) to assess ovarian reserve, and our endpoint was percentage fibroid devascularisation.”

Hacking reported a 95% dominant fibroid complete devascularisation.

“We had three groups: 100% [fibroid devascularisation], 90–99%, and less than 90%. We considered less than 90% a failure,” he said. Dominant fibroid devascularisation was below 90% for all the other embolic agents investigated,

Patients experienced significant improvements in their quality of life, with most of the 25 women involved in the study saying the treatment was “life changing”.

except for PVA, which had very similar results to GelBead. The other four agents were between 70% and 85%. However, Hacking noted that this study “is not a randomised controlled trial (RCT)”, saying “I respect the RCT data.”

Looking at total fibroid devascularisation data, Hacking comments “If you have got five fibroids or 25 fibroids, to get the 100% [fibroid devascularisation] you have to kill every last bit of every last fibroid, so that is quite a challenge.” When using GelBead, 80% of all fibroids had complete devascularisation. Of this, Hacking said, “GelBead did very well, slightly less well than PVA [85% of fibroids had complete devascularisation in this group], but there was no statistical difference with GelBead any of these other embolic agents investigated, so it is working well. It is reducing the uterus volume, it is reducing the dominant fibroids, which you would expect, and of course the symptoms have improved.”

Moreover, there was no increased permanent uterine artery occlusion, meaning that repeat procedures in cases of future fibroid regrowth are possible.

The study investigators found that 75% of patients in the GelBead cohort had bilateral uterine artery patency on MRI at three months. “Our temporary agent, Gelfoam, that we have used for decades, has a bilateral occlusion rate, at least in my hands, of just over a half, a unilateral occlusion rate of 40%, and only 5% with bilateral patency—very strange. If you look at the others though, bilateral patency even with Embospheres is only 55%; remember it is gelatine based. Bead block, Embozenes and PVA are all better [with a bilateral patency result of 94%, 85% and 75%, respectively]. GelBead is pretty good.”

However, Hacking also acknowledges that he changed his technique slightly: “I pushed the GelBead a bit deeper into the uterus, so I think I am cheating slightly compared to the Gelfoam, but those are still quite impressive figures.”

Nigel Hacking

No reduction in ovarian function

Of these results, Hacking commented: “We got good uterine and dominant fibroid reduction [37% and 46%, respectively] and no significant drop in the AMH levels, representing no significant drop in ovarian function.”

All of the patients in this study were over 40, so no conclusions can be drawn concerning fertility from this work, and Hacking advised further studies in younger women be conducted. Noting that this was “pure conjecture”, Hacking nevertheless proposed that the idea behind using a completely bioresorbable embolic agent is that “if you do not damage ovarian function, the younger women that we might be able to treat, might not only be able to conceive, but might be able to carry a healthy pregnancy.”

There was a mean reduction in the symptom score as well over the course of the study. At three months’ followup, the average UFS symptom score was 17, compared with 63 at baseline.

Additionally, the majority of patients experienced significant improvements in their quality of life, with most of the 25 women involved in the study saying the treatment was “life changing”. However, speaking of the change in quality of life observed in these patients, Hacking emphasised that this particular finding is not new: “We sort of know this already with all the embolic agents.”

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Peripheral arterial disease

Experienced endovascular specialists are not able to predict the haemodynamic significance of peripheral arterial lesions Evaluation of the functional significance of intermediate peripheral arterial stenoses should not be based solely on angiographic assessment even by experienced endovascular specialists. This is the conclusion presented by Mostafa Albayati (Department of Vascular Surgery and Interventional Radiology, Guy’s & St Thomas’ NHS Foundation Trust; King’s College London, London, UK) at the annual conference of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September, Lisbon, Portugal).

“T

he current methods used to assess severity of peripheral arterial stenoses are based on visual estimation from angiography, percentage damage of stenosis, and duplex ultrasound, which gives us some haemodynamic measure of severity, but only at rest,” Albayati told delegates. “These modalities do not provide any haemodynamic information to guide decision making.”

Therefore, Albayati suggested that endovascular specialists depart from conventional methods of assessing lesion severity based on diameter stenosis, and instead use duplex ultrasound and angiographic estimates of stenosis severity, symptoms, and restenosis.

Providing context to this advice, Albayati explained how seminal work facilitated by 014 pressure censored guidewires have enabled the measurement of fractional flow reserve (FFR). This is a measure of pressure distal to a stenosis, divided by pressure proximal to the lesion during maximum hyperaemia, and indicates the functional haemodynamic compromise of a given stenosis; in other words, the amount of blood flow that a vessel can deliver on demand, which, in the landmark FAME trials, was shown to improve lesion selection and outcome after percutaneous coronary intervention more than angiographic guided treatment would.

Albayati and colleagues hypothesised that the current practice of assessing lesion severity based on diameter stenosis does not correlate with functional haemodynamic measurements, and thus set out to test this. Speaking to the CIRSE delegates, Albayati explained that the aims of this study were three-fold: “Firstly, to determine operator agreements in visual estimates of severity of peripheral arterial stenoses. Secondly, to measure the functional severity of these lesions, and thirdly, to relate to these functional measurements to duplex ultrasound and angiographic

estimates of stenosis severity, symptoms and restenosis on follow-up.”

In this study, patients underwent duplex ultrasound and CT scanning pre-operatively as part of their standard care. Six experts then visually scored the diameter stenosis value from CT, and categorised them as either haemodynamically significant or non-significant. Patients then underwent a trans-stenotic FFR measurement during their procedure, before and after the culprit lesion was treated, and a duplex ultrasound was used to assess patency on follow-up.

Mostafa Albayati

All single, isolated stenoses in the iliac and femoral arteries of one or both legs were included in the trial.

Exclusion criteria included a previous intervention for peripheral artery disease, any patients requiring general anaesthesia, and the existence of contraindications to adenosine.

A total of 52 stenoses and 45 patients were assessed by FFR. According to Albayati, “The majority displayed the usual cardiovascular risk factors that you would expect, and were already on best medical therapy.

The indications for treatment in this group were claudication in 64%, and critical limb ischaemia in 36%.”

He continued: “We also took the opportunity to measure FFR in a further nine low grade stenoses below 30%, which were identified incidentally and

Post-treatment FFR value of less than 0.88 predicted those patients who either had a residual stenosis after treatment, or went on to develop a restenosis with a sensitivity and specificity of 75%.

FFR provides a method for assessing the functional severity of these lesions, and discriminates the clinical significance better than our standard techniques. It also objectively measures treatment success. not treated, and 13 healthy vessels from the patient’s other leg. We acquired these additional measurements in order to understand the hyperaemic pressure flow relationship across the full spectrum of the disease.”

The study investigators found that in two-thirds of the 52 lesions under scrutiny, there was some disagreement between operators and lesion scoring.

In a graph plotting the percentage stenosis diameter per lesion, the more extreme lesions—those below 30% and tighter ones above 80%—had good agreement between operators and lesion scoring. However, Albayati said, “In the intermediate range, there is much greater variation. Overall, operators unanimously agreed on haemodynamic severity in 33% of lesions.”

Following intervention, the same operators recategorised the same lesions, but in addition to the CT scan were given the FFR value. This significantly improved agreement between operators. This is explained by the fact that when looking at the pressure-flow relationship of the stenoses, the trans-stenotic pressure gradients are clustered together during resting flow, as they are of similar value. This particularly occurs in the intermediate range of stenoses, which require hyperaemia in order to amplify the pressure gradients ad unmask the haemodynamic severity.

The investigators ascertained that FFR relates better to symptom severity—in other words, whether a patient has claudication or critical limb ischaemia. Elaborating, Albayati said: “We followed all patients up with duplex ultrasound, and after a median follow-up of three months, we found that a post-treatment FFR value of less than 0.88 predicted those patients who either had a residual stenosis after treatment, or went on to develop a restenosis with a sensitivity and specificity of 75%.”

Summarising his findings, Albayati

concluded: “Large variations exist between vascular specialists in severity assessment of peripheral arterial stenoses. FFR provides a method for assessing the functional severity of these lesions, and discriminates the clinical significance better than our standard techniques. It also objectively measures treatment success.”

So are interventionists ready to use FFR in peripheral disease more often?

Albayati thinks so, but is cautious in his answer, explaining that with only 45 patients and 52 lesions, this is an exploratory study. “From my understanding,” he said, “I do not know of any centre that incorporates FFR into routine clinical practice, but the trial data in the coronaries is compelling.

It has now been written in to some standard guidelines, and forms part of percutaneous coronary intervention procedural decision making.”

However, there are still some difficulties with the invasiveness of this technique, as Albayati explained: “However, it still requires invasive arterial access on lesions that may be haemodynamically nonsignificant. The next phase of my work is to non-invasively estimate FFR using computational fluid dynamics. In this example of a patient with claudication due to a common iliac stenosis, you can see that the computed FFR value compares well with that measured invasively.”

This technology utilises computational fluid dynamics, and is already used in the aviation industry to test aeroplanes before any components of the plane are build. Albayati calls this a “robust technology,” that he believes “can be used effectively to solve haemodynamic problems.”

However, he conceded that one of the limitations is the image quality, as the 3D haemodynamic model is built on the CT scan.

The British Heart Foundation and the Biomedical Research Centre at King’s College (London, UK) funded this study.

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Drug-coated balloons

ADVERTORIAL

Interim results of the Lutonix drug-coated balloon in a complex patient cohort for below-the-knee lesions “very promising” In a complex patient population with advanced, symptomatic below-theknee peripheral artery disease, treatment with the Lutonix drug-coated balloon (BD) led to excellent freedom from all primary safety endpoints, including 30-day all-cause death, above-ankle amputation, and major reintervention. These interim real world data of the Lutonix global drugcoated balloon registry at 12 months, were presented by Dierk Scheinert (Leipzig, Germany) at the Cardiovascular and Interventional Radiological Society annual meeting (CIRSE; 22–25 September, Lisbon, Portugal).

IN THE PROSPECTIVE, multicentre, single arm Lutonix global registry, 371 infrapopliteal lesions were treated with the Lutonix drug-coated balloon (DCB). Patients were Rutherford category 3, 4 or 5; two-thirds were diabetics, three quarters suffered from critical limb ischaemia (CLI), and 65% were Rutherford category 5. Mean lesion length was 12cm, with over 20% exhibiting severe calcification.

The interim data presented by Scheinert at CIRSE is highly promising. Out of 244 patients, only 5.4% had a major amputation within one year, a result which Scheinert describes as “very reassuring for this complex patient population.”

All-cause mortality was around 12% after one year of follow-up, and there were no unexpected device related events reported.

Furthermore, there was 99.7% freedom from reintervention for distal embolization in the patient cohort.

Improvement in Rutherford clinical category (RCC) was also marked: 80% of patients exhibited a clinical improvement

Dierk Scheinert

by≥1 RCC, and almost two-thirds demonstrated an improvement by≥3 RCC. “As the clinical outcome is of utmost importance for the patient,” Scheinert says, “I was most surprised by the excellent clinical results with improvement of Rutherford clinical category in 80% of patients. Further, the observed 80% freedom from target lesion revascularisation rate

at one year is very promising, as patency failures are observed frequently after infrapopliteal interventions, in particular in diabetics and CLI patients.”

Speaking to Interventional News of the results’ significance, he states, “Patients with below-the-knee (BTK) disease suffer from high failure rates with currently available treatment modalities, as standard balloon angioplasty for long, complex infrapopliteal lesions is limited by high restenosis rates. As innovations are urgently needed, the Lutonix DCB could become a new tool to improve outcomes in this special patient population. Of course, the results of the Lutonix below-the-knee randomised trial are highly anticipated, and final results of both studies could have a major impact on clinical practice.”

The Lutonix DCB is coated with excipients polysorbate and the endogenous metabolite sorbitol, as well as paclitaxel at a density of 2μg/mm2. Extensive in vitro and in vivo testing has previously demonstrated an excellent downstream particulate safety, with minimal risk of embolization.

Scheinert explains how this is particularly important in BTK interventions, where compromised outflow to the foot arteries is often present. He further explains how “a good balance was achieved between adhesion of the coating to the balloon during handling and advancement to the lesion and release of the coating to the vessel wall upon deployment”.

According to Scheinert, patients with long infrapopliteal lesions may benefit most from treatment with the Lutonix DCB, “as restenosis rates are high, especially in diabetics.” Importantly, he notes that target lesion revascularisation rates were comparable for diabetics and non-diabetics.

Recruitment for BTK studies is typically difficult, as patients are often older, suffering from multiple co-morbidities. Ensuring follow-up is also a major challenge, lending greater significance to the results of the present study.

Scheinert also emphasised the importance of using real world registries, arguing “results from real-world patients are important to ensure safety and efficacy of new devices for all treated patients”.

So far, an extensive clinical trial programme showed the benefit of using a Lutonix DCB in the treatment of obstructive lesions in the superficial femoral artery, while confirming minimal risks with the addition of the drug compared to standard balloon angioplasty. Now the same formulation is under investigation for BTK patients and the vascular community eagerly awaits the results of the Lutonix randomised trial, anticipating a potentially major impact on current standard care.

Based on his presentation Scheinert summarises: “As these first results are promising, we hopefully can add the Lutonix DCB to our armamentarium for below-the-knee interventions soon.”

Late-breaking trial shows similar outcomes for severely versus non-severely calcified lesions following treatment with Stellarex DCB Data from a study seeking to determine the impact of severe calcification and 12-month outcomes of femoropopliteal disease treatment using the Stellarex drug-coated balloon (DCB; Phillips) were presented by Fabrizio Fanelli, Careggi University Hospital, Florence, Italy, at the CIRSE 2018 annual meeting. Remarkably similar outcomes were achieved with the device in severely calcified lesions that were amenable to predilation, versus those without severe calcium.

“W

e know that calcium is the enemy for all endovascular procedures,” noted Fanelli. He acknowledged that although the implications of severe calcification are known—in relation to the occurrence of suboptimal dilation and the ability of calcium to act as a barrier for drugs—the impact of calcium on drug coated balloon performance has yet to be fully examined. For instance, previous trials have demonstrated calcium to be a potential barrier to optimal drug absorption; circumferential calcium being the strongest contributor, resulting in the reduction of patency rates.

The authors carried out a prospective study in which patients were pooled from the ILLUMENATE Global (full cohort of the single-arm study; n=371) and ILLUMENATE Pivotal (drug-coated balloon arm of the randomised trial; n=200). Patency, determined by duplex ultrasound, was assessed at 12 months. Both trials included independent oversight by a Clinical Events Committee and core laboratories analysed

angiographic and duplex ultrasound images.

At 12-months, primary patency rates were similar between groups; 82% in the non-severely calcified group compared with 80% in the severely calcified group (log-rank p=0.06). Additional outcomes mirror this similarity; freedom from primary safety events was 93% and the rate of clinically-driven target lesion revascularisation (TLR) was 7% in both cohorts. The rate of 12-month major adverse events was 7.3% and 7.8% (in non-severely and severely calcified lesions, respectively).

Regarding the procedural characteristics, predilatation maximum pressure was higher (9.5 vs.

8.8atm, p=0.005) and the total drug coated balloon inflation time was longer (3.4 vs. 3.9 minutes, p=0.005) in the severely calcified group. Additionally, dissection (>grade C) and provisional stenting rates were found to be similar between groups.

Overall, 556 patients were included in the study, with 242 severely calcified and 314 non-severely

calcified lesions. No significant demographic differences were observed in the two groups. However, patients with severely calcified lesions were older and tended to have a higher rate of comorbidities. Severe calcification, prior to contrast injection or digital subtraction angiography, was prospectively defined as “radioopacities noted on both sides of the arterial wall and extending more than one cm of length”.

In light of the findings, Fanelli concluded that similar 12-month outcomes can be achieved with the Stellarex drug coated balloon in severely calcified lesions that are amenable to pre-dilatation. The study also confirmed that severe calcium requires longer and stronger inflation, and by doing so, similar stenting rates can be achieved regardless of whether a lesion is severely or non-severely calcified.

Speaking to the CIRSE audience about reasons for the similar patency rates that were observed, Fanelli said: “This can be attributed to the better preparation of the vessel [and] to the characteristics of the balloon itself”.

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AV access

13

Covered stent provides greater patency than angioplasty alone in AV fistulae

The Covera vascular covered stent (BD) has a superior six-month primary patency rate than standard balloon angioplasty, with an equivalent safety at 30 days, when used in the treatment of stenotic lesions in arteriovenous (AV) fistula patients. Data from AVeNEW, the first level-one clinical trial on the use of a covered stent to treat these patients, were reported at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September 2018, Lisbon, Portugal).

P

rincipal investigator Bart Dolmatch (Department of Radiology, Palo Alto Medical Foundation, Mountain View, USA) told delegates: “The primary endpoint was six-month target lesion primary patency, and in the covered stent group the primary patency was 78.7%, whereas in the angioplasty group it was 47.9%; that is greater than 30% difference at six months, with a P value that was highly significant at <0.001.”

The primary safety endpoint was measured by freedom from an event resulting in intervention, hospitalisation, or death at 30 days. The study found that use of the vascular covered stent was non-inferior to percutaneous transluminal angioplasty (PTA) alone.

Dolmatch said: “You can see a comparable safety profile for both the covered stent group and the angioplasty group, with a high significance for showing non-inferiority of the Covera stent graft compared to angioplasty.”

The prospective, international multicentre study randomised 280 patients (1:1) to receive either balloon angioplasty or angioplasty plus the Covera stent graft for the treatment of stenotic lesions in the venous outflow of upper extremity AV access circuits in patients dialysing with an autogenous fistula. The Covera vascular covered stent is a polytetrafluoroethylene- (ePTFE) covered selfexpanding stent. Patients were treated at 24 centres

in the USA, Europe, Australia, and New Zealand, and exhibited greater than 50% stenosis in the venous outflow of the AV access circuit, with clinical or haemodynamic evidence of fistula dysfunction.

Dolmatch explained: “The study included the typical sort of dialysis patients we see across the globe, with a mean age of about 62 to 63 years, slightly more weighted towards males than females, and about 30% of patients had a BMI [body mass index] that was… in the obese or heavy range. The patients had typically brachial cephalic or brachial basilic fistulae.”

Secondary measures included access circuit primary patency and the number of reinterventions needed to maintain patency. The number of target lesion reinterventions for the covered stent group was 0.3 for the six-month period, compared to 0.8 for the angioplasty group. Acute technical and procedural success rates were also high in the stent group, at 100% and 98.6%. “Overall,” said Dolmatch, “the procedure was extremely successful, with a very low complication rate.”

He added: “All of the stent graft sub-analyses showed superior outcomes compared to balloon angioplasty—for instance, the use of treatment in the cephalic vein arch, with much better outcomes with the stent graft group compared to angioplasty.” The vascular covered stent had a success rate of 78.7% in the cephalic vein arch versus 38.3% for PTA alone, a

The procedure using the Covera vascular covered stent was extremely successful, with a very low complication rate. difference of 37%. Target lesion primary patency was maintained in 86% of de novo lesions and 77.7% of restenosed lesions in the stent group, compared to 65.6% and 40%, respectively, for angioplasty alone.

The most commonly used diameters of stent graft used in the study were nine and 10mm, and stent graft lengths were typically between 40 and 60 diameters.

Follow up in the AveNEW trial is ongoing for two years, and Dolmatch expressed his optimism about future results. “The divergence [in primary patency] is really starting at about 60 days and continuing on to 180 days. This is six-month data. We are looking forward to seeing 12-month, 18-, and 24-month data showing the superiority of stent graft treatment of the stenoses in fistulae, compared to angioplasty.”

Paclitaxel DCB no better than placebo to treat stenosis in patients with arteriovenous fistulae In a study evaluating the efficacy of a drug-coated balloon (DCB) in inhibiting restenosis and ensuring long-term patency in patients with arteriovenous fistulae (AVF), the paclitaxel DCB did not show superiority to a placebo high pressure balloon at 12 months’ follow-up. Manuela Moreno-Ramírez (Department of Nephrology, Juan Ramón Jiménez Hospital, Huelva, Spain) presented these results of the EffPAC trial at the Cardiovascular and Interventional Radiological Society of Europe annual meeting (CIRSE; 22–25 September, Lisbon, Portugal).

THE TRIAL WAS an investigatorinitiated, prospective, multicentre, double blind, randomised study conducted across four Spanish hospitals. One hundred and seventy-eight dialysis patients included in the study were divided into two groups: those treated with a paclitaxel DCB—the CE-marked Passeo-Lux 18 (Biotronik )— and those treated with an uncoated high pressure balloon, who were recipients of a placebo. The placebo involved the use of a safe and biocompatible non-hydrophilic excipient called butyryl-tri-hexyl (BTHC) that facilitates the delivery and absorption of the drug from the vessel wall.

Moreno-Ramírez emphasised the need for new procedures to treat stenosis, telling the CIRSE audience that “Difficulties with vascular access are an important source of morbidity and mortality in haemodialysis patients. Stenosis could be treated with percutaneous transluminal angioplasty

(PTA), but the primary patency rate is only 40–50% at one year—hence, new procedures are needed.” Thus, the study investigators were interested in researching the paclitaxel DCB as a possible alternative treatment strategy.

However, neither the primary nor the secondary endpoints of this study were met, with the paclitaxel DCB failing to demonstrate superiority over the placebo.

In addition to the primary endpoints of safety and efficacy, Moreno-Ramírez and colleagues sought to determine differences in survival rates. They found none. Despite the mean survival in the DCB group being higher, at 265 days versus 237, this was not statistically significant. There were therefore no statistically significant differences in survival at 12 months’ follow-up in terms of stenosis location, type of arteriovenous fistulae, or previous angioplasty. MorenoRamírez summarised: “We think this

Manuela Moreno-Ramírez

result is not clinically relevant.”

This finding is the same as that of another multicentre clinical trial with

a significant sample size, conducted

by Scott Trerotola and colleagues (Department of Radiology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, USA).

Trerotola concluded in 2018 that, despite finding a slight improvement in survival using the Lutonix DCB (BD) compared to a placebo at six months’ follow-up, the difference was not statistically significant. However, several other previous studies, such as the IN.PACT trial by Panagiotis Kitrou (University of Patras, Patras, Greece) and colleagues— investigating at the In.Pact Admiral DCB (Medtronic) versus a placebo—contradict this conclusion, finding a definite improvement in survival with a DCB compared to uncoated alternatives.

However, Moreno-Ramírez does believe it is important to note that the global survival rates in her team’s study at 12 months are superior to that in previous published studies, at almost 60%. Moreno-Ramírez attributed this to the use of a high pressure balloon for angioplasty. Clarifying her methodology, Moreno-Ramírez explained that for every patient enrolled in the present study, both those in the DCB arm and the placebo arm, the first angioplasty utilised a high pressure balloon. Next, Moreno-Ramírez and colleagues carried out a fistulography to discover if the first angioplasty had been effective.

Allocation into the two different randomised groups occurred then, before a second angioplasty with DCB.

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Peripheral arterial disease

Rivaroxaban receives peripheral arterial disease indication in Europe and USA Rivaroxaban (brand name Xarelto, Bayer) has received approval from the US Food and Drug Administration (FDA) and the European Commission to reduce risks in peripheral arterial and chronic coronary disease patients. The oral anticoagulant is indicated in combination with aspirin, and is now the first and only Factor Xa inhibitor approved for patients living with these conditions.

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oth approvals are based on results from the landmark COMPASS trial, which showed a significant 24% reduction of the risk of major CV events in patients with chronic coronary arterial disease (CAD) and/or peripheral arterial disease (PAD) with a 2.5mg vascular dose of rivaroxaban twice daily plus aspirin 100mg once daily, compared to aspirin alone. This finding was driven by a 42% reduction in stroke, 22% reduction in cardiovascular (CV) death and 14% reduction in heart attack. The risk of major bleeding was significantly higher in patients taking the rivaroxaban/aspirin regimen compared to aspirin alone, with no significant increase in fatal or intracranial bleeds.

Derek Connolly, consultant interventional cardiologist at Birmingham City Hospital, (Birmingham, UK) and COMPASS trial investigator commented: “Cardiovascular diseases are one of the leading causes of death in the UK, and coronary artery disease and peripheral arterial disease represent a major public health burden—despite many advances in the area of cardiovascular care, CAD and PAD have remained an area of unmet need. Even with currently available treatments for secondary prevention, patients remain at an unacceptably high risk of thrombotic events which can lead to disability, loss of limb and death. This was the biggest study of rivaroxaban to date, and now that it is licensed for these conditions, it provides UK clinicians with a new

option for treating CAD and PAD.” Lars Bruening, CEO Bayer UK & Ireland, said: “The story and momentum behind the COMPASS data continues to grow—from the study being stopped one year early for overwhelming efficacy, the presentation of the results themselves at the European Society of Cardiology congress last year, and now to this exciting news from the European Commission.

Ten years ago this October saw Bayer just starting out on the Xarelto journey with the first indication in orthopaedics—and this year we welcome our eighth

indication for the management of patients with CAD and PAD in the UK. It is especially exciting to see the continuing impact that Xarelto will have on patients with PAD, most of whom have concurrent CAD, as it has been many years since a new medical therapy has been proven in this high risk patient population.”

Following the licence approval across Europe, the new indication will be submitted to the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) for review for routine reimbursement across the UK. “Despite the use of guideline-recommended therapies, patients with chronic CAD and/or PAD remain at risk of having a devastating and irreversible CV event,” said Paul Burton, vice president, Medical Affairs, Internal Medicine, Janssen Scientific Affairs, LLC. “The new Xarelto vascular 2.5mg dose, when used with aspirin, represents a true breakthrough for patients with chronic CAD and PAD.” “Treating patients with aspirin only is simply not enough to address the underlying thrombotic risk that comes with chronic CAD and PAD,” said Kelley Branch, associate professor in Cardiology, University of Washington, Seattle, USA. “As we saw in the COMPASS trial, the dual pathway approach of aspirin and the 2.5mg, twice-daily dose of Xarelto can help significantly reduce the risk of CV events in these populations.”

Novel approach in treating stenotic peripheral arteries shown to be safe and effective Twelve-month data prove that intravascular lithotripsy; a novel approach using pulsatile sonic pressure waves to modify intimal and medium calcium in stenotic peripheral arteries, is a safe and effective treatment option. This is the result of the Disrupt PAD II trial, presented by Andrew Holden, Auckland Hospital, Auckland, New Zealand, for the first time at the Cardiovascular and Interventional Radiological Society of Europe annual meeting (CIRSE; 22–25 September 2018, Lisbon, Portugal).

Andrew Holden

SPEAKING TO THE CIRSE audience, Holden explained that acute results were strong, with compelling safety data showing a final residual

stenosis of 24.2%, with a high acute gain of 3mm and minimal vascular complications. In addition, Holden implied that the primary safety profile was “very good”, given that the only major adverse event though to 12 months was a dissection that occurred at the time of procedure.

DISRUPT PAD II was a nonrandomised, multicentre study that enrolled 60 patients with complex, calcified peripheral arterial stenosis at eight sites. Patients were treated with the peripheral intravascular lithotripsy system (Shockwave Medical), and followed out to 12 months.

Calcium burden was significant, with 85% of the patient cohort exhibiting severe calcification involving both sides of the arterial wall (using the PARC definition; 50% of patients had severe calcification using the pre-defined Core Lab

definition) and an average length of calcium of 98.1%.

The study investigators report high acute gain (following low pressure) in terms of the reduction of pre-procedural severity of stenosis, as well as crosssectional area gain. This resulted in low dissections and minimal use of stents in this calcified population.

Additionally, 12-month primary patency was 54.5%, with a freedom from target lesion revascularisation rate of 79.3% in a stand-alone therapy.

Primary patency outcomes were shown to improve by optimising the procedural technique: appropriate balloon sizing and intravascular lithotripsy therapeutic coverage resulted in the increased primary patency of 62.9% at 12-months follow up, with freedom from target lesion revascularisation being 91.4%.

Target lesion patency, the primary

effectiveness endpoint of the study defined as freedom from ≥50% restenosis, was found to be 69.8% (30/43 patients), as measured by duplex ultrasound. Clinically, improvement in functional outcomes were sustained through to 12-months, in terms of both the ankle-brachial index and Rutherford scores.

In conclusion, the DISRUPT PAD II trial remains the first and only core lab adjudicated study to exclusively enrol and follow out to 12-months, heavily calcified lesions. Furthermore, Holden maintained that when intravascular lithotripsy is utilised as a standalone therapy in this complex patient population, primary patency outcomes improve.

Regarding the next steps in clinical development, Holden stated: “Importantly, the DISRUPT PAD III trial is recruiting… a much larger, 400 patient trial looking to evaluate the role of intravascular lithotripsy in the setting of drug coated therapy.” Specifically, patients have been randomised to intravascular lithotripsy in combination with the IN.PACT drug-coated balloon (DCB; the treatment arm) or plain balloon angioplasty and DCB (the control arm), in order to address plaque modification in heavily calcified arteries. “This will be a very important trial to establish the benefit of intravascular lithotripsy in the DCB era,” Holden concluded.

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Drug-eluting stents

Eluvia outperforms Zilver PTX in IMPERIAL 12-month results The Eluvia drug-eluting vascular stent system (Boston Scientific) shows superior primary patency compared to the Zilver PTX drugeluting stent (Cook Medical), concludes the 12-month follow-up of the IMPERIAL randomised controlled trial. These data were presented for the first time at the Cardiovascular and Interventional Radiological Society of Europe 2018 meeting (CIRSE; 22–25 September, Lisbon, Portugal).

THE IMPERIAL TRIAL was also presented at the Transcatheter Cardiovascular Therapeutics (TCT) conference (25–29 September, San Diego, USA) and were accompanied by simultaneous publication in The Lancet.

The IMPERIAL trial was a prospective, randomised, singleblinded, multicentre global study aimed at comparing the effectiveness and safety of the Eluvia with Zilver PTX for treatment of symptomatic femoropopliteal artery lesions (lesion length 30–140mm, Rutherford category 2–4).

Presenting the results, Stefan MüllerHülsbeck (Flensburg, Germany; the European primary investigator) told the CIRSE audience: “Clinical outcome rates were similar between groups, but with half the revascularisation rate for

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Eluvia.” For instance, the Eluvia stent had a target lesion revascularisation rate of 4.5%, in contrast to 9% observed within the Zilver PTX cohort.

Additionally, the Eluvia stent was found to be more effective than the Zilver PTX, with a primary vessel patency of 88.5% at 12-months versus 79.5% after the same time-frame.

Primary vessel patency is defined as a core lab-assessed duplex ultrasound peak systolic velocity ratio of ≤2.4 in the absence of clinically-driven target lesion revascularisation or bypass of the target lesion.

Both the Eluvia stent system and the Zilver PTX—which are designed to restore blood flow in the superficial femoral and proximal popliteal arteries—feature a drug-polymer combination intended to allow for the sustained release of paclitaxel. This

Stefan Müller-Hülsbeck

drug can prevent restenosis of the vessel.

However, the presence of a polymer (a biostable fluorinated polymer matrix) contained within the Eluvia stent allows for a lower dose of paclitaxel, which is indicative of the main difference between the two stents.

Speaking to the CIRSE audience about the reasons for the findings, Müller-Hülsbeck alluded to the presence of the polymer being the “key to success”.

“These impressive clinical outcomes suggest that sustained elution of paclitaxel, delivered by the Eluvia stent, better matched the timing of restenosis in the SFA that can occur

months later, thereby reducing the need for repeat interventions,” said William Gray, co-principal investigator of the IMPERIAL trial. “Based on these findings, we believe that the Eluvia stent can be a preferred therapy option when treating patients with arterial blockages in the superficial femoral or proximal popliteal arteries.”

Off the back of data from the MAJESTIC trial, which evidenced long-term freedom from revascularisation at three years, the Eluvia stent system received the CE mark in early 2016. With a primary patency rate of more than 96%, the MAJESTIC trial results represented the highest 12-month primary patency reported for an interventional treatment of femoropopliteal artery lesions among comparable trials, according to Boston Scientific.

The Zilver PTX drug-eluting stent also has a wealth of strong clinical data supporting its efficacy. In 2009, the device was the first CE mark-approved drug-eluting stent designed specifically to treat severe blockages in the superficial femoral artery. Five-years results from the largest and longestrunning clinical trial of a drug-eluting stent for treating peripheral arterial disease, published in 2014, evidenced long-term patency for patients treated with the Zilver PTX. This 2014 study compared the Zilver PTX with a bare metal stent, and confirmed the “sustained benefit” of the paclitaxeleluting stent.

Five-year evaluation of Zilver PTX stent in a real-world population continues to show favourable outcomes Five-year results from a Japanese post-market surveillance study aimed at evaluating the Zilver PTX drug-eluting stent (DES) in a real-world population show consistently positive outcomes. The findings were presented for the first time at the Cardiovascular and Interventional Radiological Society of Europe 2018 meeting (CIRSE; 22–25 September, Lisbon, Portugal), by Kimihiko Kichikawa, Nara Medical University Hospital, Kashihara, Japan.

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ccording to Kichikawa, the use of the Zilver PTX DES (Cook Medical) in treating patients with femoropopliteal lesions have so far elicited favourable outcomes. Therefore, Kichikawa and colleagues took a multicentre, prospective approach to the post-market surveillance study that evaluated the DES in a real-world patient population.

A total of 904 patients with 1,080 lesions were enrolled in 95 institutions in Japan and consecutively treated. Comorbidities were present in the patient population, including a high incidence of diabetes (59%), chronic kidney disease (44%), and critical limb ischaemia (21%).

Stent integrity was assessed by radiography, with site-reported fractures were reviewed by a radiographic core laboratory for classification of fracture type. The

investigators noted any clinically driven target lesion revascularisation, defined as re-intervention performed for ≥50% diameter stenosis after recurrent clinical symptoms of peripheral arterial disease. Furthermore, clinical benefit was defined as freedom from the following: persistent or worsening claudication, rest pain, ulcers, or tissue loss.

The investigators found that lesions were complex; their average length at 14.6mm, with 44% found to be totally occluded and an additional 19% involving instent restenosis. Clinical follow-up that occurred through five years was obtained for >90% of eligible patients.

The five-year outcomes indicated that the rates of freedom from target lesion revascularisation were 74.2%, while the clinical benefit indicated for the patient population was 68.2%. Speaking to the CIRSE

The data show consistently good results in a challenging patient population, including those with diabetes, renal failure, long lesions, in-stent restenosis, or critical limb ischaemia.

Kimihiko Kichikawa

audience, Kichikawa said these figures were indicative of: “Consistently good results in a challenging patient population including those with diabetes, renal failure, long lesions, in-stent restenosis, no runoff or critical limb ischaemia.” The ankle-brachial index and Rutherford scores further indicated that clinical improvement was maintained over-time, after the rapid increase in Rutherford scores one year into the trial.

In conclusion, Kichikawa said: “Patient population and lesion characteristics become more challenging in real-world, all-comer studies”. However, he reiterated that the results of the study continue to show positive long-term outcomes and demonstrate the benefit of the Zilver PTX DES across a broad patient population.

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Interventional radiology

The future of interventional radiology rests on the creativity and innovation that founded the discipline Described by her supervisor Glen Schlaphoff (Sydney, Australia) as “a perfect example of a young up and coming interventional radiologist”, Sindhura Nirmalarajan is a Radiology registrar at the Prince of Wales Hospital, Sydney, Australia. At the 2018 annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September, Lisbon, Portugal), she was honoured with the Magna cum Laude e-poster award for her work on prostate artery embolization. Here, she discusses this research with Interventional News, as well as why she is excited for the future of interventional radiology (IR).

What is your reaction to winning the prestigious e-poster award at CIRSE?

the establishment of outpatient clinics, primary clinical responsibility for patients, and collaboration with other disciplines to provide care for a larger number of increasingly complex patients. Furthermore, the need for standardisation of training is recognised and has resulted in many Australian IRs undertaking the EBIR [European Board of Interventional Radiology] certification. For trainees in Australia, this is a great time to be involved in helping to shape the future of this dynamic specialty.

I submitted this project through the CIRSE trainee support programme and was very excited to hear the poster was accepted for presentation alongside many high calibre projects.

Receiving the Magna cum Laude award took me completely by surprise and I feel incredibly honoured by this recognition. I am grateful for the opportunity to have presented this work and for the support of my supervisor Glen Schlaphoff (South Western Sydney Clinical School, Sydney, Australia).

Would you summarise the findings of the research presented in your e-poster?

Prostate artery embolisation (PAE) is emerging as an effective treatment option for lower urinary tract symptoms caused by benign prostatic hyperplasia. One of the technical challenges of this procedure is accurately identifying variant pelvic arterial anatomy. We reviewed the angiograms of 202 pelvic sides and classified the branching pattern of the internal iliac and prostate arteries using the framework of existing angiographic classification systems.

We found the incidence of anatomical variants in our series from a single Australian institution (Liverpool Hospital, Sydney) to be comparable to the incidence reported in previous studies. Despite the high degree of variability, the origin of the prostate artery could be classified into one of four types in 96% of our cases.

How will these findings influence clinical practice?

This poster serves as an educational resource that provides a systematic approach to understanding and identifying complex and variable pelvic arterial anatomy. In particular, it provides a pictorial overview of the range of arterial variants related to PAE and potential intra/extraprostatic anastomoses. Ultimately, this awareness improves technical success, reduces fluoroscopy time and minimises the risk of non-target embolization.

Why is this an exciting time to be involved in interventional radiology?

IR is founded on creativity and innovation and this enables the

Sindhura Nirmalarajan

specialty to meet the increasing demand for minimally invasive treatment options, which are effective, safe and have reduced recovery times.

There has been a shift in the practice of IR in the modern day, with an increasing recognition that technical expertise is only one component of the larger clinical skillset of an IR. The continued progression of IR into an increasingly integrated clinical specialty combined with the development of new technical innovations makes this an exciting time to be involved in IR.

You currently practice in Sydney, Australia. How does the Australian healthcare system help and/or hinder your work and how would you describe the IR scene in Australia for up and coming radiologists?

Australia is fortunate to have one of the world’s leading healthcare systems.

The availability of universal healthcare means that IR services in public tertiary centres are highly accessible.

IR is embedded in the multidisciplinary healthcare system and there is constant collaboration with other specialties, such as in the settings of oncology, trauma, paediatrics, and many others. As an Australian trainee, this provides a diverse and robust mix of cases and exposure to the breadth of interventional radiology.

There is a widespread recognition of the importance of achieving subspecialty status for IR in Australia.

An essential step in this complex process is increasing the clinical focus of IR. This has seen a shift towards

There still exists a gender imbalance in this field, with more male IRs than female.

Why do you think this is and what do you think should be done to address/change this?

There is a growing focus on the disproportionately small number of female IRs compared to the numbers of female medical graduates and trainees in other traditionally maledominated specialties. Several studies have explored the reasons for this disparity and have highlighted multiple contributing and inter-related factors including: the relatively few women in leadership roles, an entry pathway via diagnostic radiology, and the misconceptions surrounding radiation exposure.

Personally, I feel that a potential avenue to address this gender disparity and also recruit individuals (both

male and female) who are motivated to pursue a career in IR would be to increase the profile of IR in medical schools and set out a clearly structured IR training programme that builds clinical and procedural expertise alongside diagnostic training. I believe that cultivating an interest in IR at the medical school level could result in a more balanced proportion of female IRs that is more reflective of the numbers of female medical graduates.

I hold this belief because I found that an early exposure to IR in medical school was pivotal in forming my interest in this field. I completed a diagnostic Radiology term at Johns Hopkins Hospital in my third year of Medicine and returned for an IR elective in my sixth year. The elegant solutions to tricky scenarios, the broad scope of practice and the effective, precise treatments that IR could provide were a revelation to me. There were several female IRs working in the department at the time and, looking back, I believe it was this early exposure to IR and the diversity of the team that helped me to see this field as a future career path.

What do you think the next generation of IRs will bring to the discipline?

I think the strength of the next generation of IRs will be to enter the training programme directly from our clinical foundation years and to maintain and build our clinical acumen throughout our training.

I believe that bringing in new perspectives with a steady influx of young trainees and increasing collaboration between IRs and other disciplines will keep the specialty progressing at the cutting edge of medicine.

Cultivating an interest in IR at the medical school level could result in a more balanced proportion of female IRs that is more reflective of the numbers of female medical graduates.

IR is founded on creativity and innovation and this enables the specialty to meet the increasing demand for minimally invasive treatment options, which are effective, safe and have reduced recovery times.

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New horizons

ADVERTORIAL

CASE REPORT: SFA-CTO Recanalization by using the novel 0.035” UltraScoreTM Focused Force PTA Balloon and DCB

Ralf Langhoff, chief, Angiology/Vascular Medicine, Sankt Gertrauden-Krankenhaus, Berlin, Germany, reports on a case in which his team used a novel 0.035” UltraScore™ Focused Force PTA Balloon (Bard, now BD) as an adjunctive therapy with the LUTONIX® drugcoated balloon (DCB) to recanalise a chronic total occlusion (CTO) in the superficial femoral artery (SFA).

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68-year-old female was referred to our vascular center for intermittent claudication primarily in the right leg (Rutherford category 3). She is a current smoker with additional risk factors for atherosclerosis, which are arterial hypertension and dyslipidemia with high cholesterol levels. She had a pain free walking distance below 50 meters, with an Ankle Brachial Index (ABI) of 0.63 on the right side.

After the referring angiologist performed a duplex examination, the test revealed a diseased SFA from the origin of the artery with an occlusion at the distal end. The total length of the diseased segment was 260mm (Fig. 1).

To avoid long segment stenting and to prepare the vessel for better drug-uptake, we intended to intraluminally cross the occlusion and follow with a dedicated scoring balloon for percutaneous transluminal angioplasty (PTA) and vessel preparation.

We used a cross-over access from the left transfemoral with a 6F Fortress Introducer Sheath, 45cm length (Biotronik) and passed the lesion with a 0.035” GLIDEWIRE® , 260cm length (Terumo).

As support, we used a 4F multi-purpose catheter, TEMPO AQUA ® (Cordis, now Cardinal Health).

Subsequently, vessel preparation was performed with the novel Ultra S core™ 5mm x 200mm scoring balloon (Bard/BD), which runs on a 0.035” wire (Fig. 2). The intention of vessel preparation is to minimize the risk of dissections, and maximize luminal gain to prepare the vessel for local drug delivery and/or stents.

The balloon was inflated slowly, which allowed the wires to provide concentrated force on the diseased vessel wall. This focused force dilatation led to a controlled plaque fracture, improved luminal gain. Additionally, the objective was to limit risk of major dissections (SOGA 2018) as severe dissections are related to negative longterm outcomes in femoro-popliteal interventions (FUJIHARA 2017). After seeing a very good and promising result after the use of the Ultra S core™ balloon, we decided to use DCBs to deliver paclitaxel to the entire lesion.

Furthermore, there is the idea that by using scoring elements during vessel preparation the drug-uptake of DCBs can be increased and optimized (CREMERS 2013). We used two 5mm x 150mm LUTONIX ® DCBs (Bard/BD) with a 1cm overlap to avoid a geographical miss. We chose a longer balloon inflation time of three minutes

Figure 8 Posteroanterior view

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

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because we revealed a short, minor dissection in the former occluded part of the lesion. We decided against provisional stenting because results of the large DCB trials reported strong effects of positive remodeling after application of paclitaxel to the vessel wall via a balloon (TEPE 2013).

Control angiography demonstrated a very good result, with a small minor dissection which was not flow limiting in several projections.

The intervention was finished without any complications and a good outflow (Fig. 3). We used a MYNXGRIP ® device (Cordis/Cardinal Health) for hemostasis and vessel closure.

After the case, the patient was free of any ischemic pain while walking.

Figure 11

References 1. Soga Y, Ando K. Effect of an NSE PTA balloon in experimental lesion models. Cardiovasc Interv Ther. 2018 Jan;33(1):35–39.

2. Fujihara M, et al. Angiographic dissection patterns and patency outcomes after balloon angioplasty for superficial femoral artery disease. J Endovasc Ther. 2017;24:367–75.

3. Cremers B, et al. Inhibition of neo-intimal hyperplasiain porcine coronary arteries utilizing a novel paclitaxel-coated scoring balloon catheter. Catheter Cardiovasc Interv. 2014 Dec 1;84(7):1089–98.

4. Tepe G, et al. High-grade, non-flow limiting dissections do not negatively impact long-term outcome after paclitaxel-coated balloon angioplasty: an additional analysis from the THUNDER study. J Endovasc Ther.

2013;20:792–800.

Interventional oncology established in “mainstream” cancer care with world-first clinical symposium The world-first collaboration between interventional oncology (IO) and radiation oncology, embraced by the Trans-Tasman Radiation Oncology Group (TROG), continues to bear fruit, with the inaugural Clinical Interventional Oncology Symposium to be held in Melbourne next March. The two-day event will feature in the TROG annual scientific meeting at the Melbourne Cricket Ground on 14–15 March 2019, Melbourne, Australia.

THE INAUGURAL CLINICAL Interventional Oncology Symposium will be a dedicated workshop on all aspects of clinical oncology relevant to interventional radiologists.

Internationally renowned oncology experts Constantinos Sofocleous (Memorial Sloan Kettering Cancer Center, New York, USA), Andreas Adam (Guy’s and St Thomas’ Hospital, London, UK) and Lizbeth Kenny (Royal Brisbane and Women’s Hospital, Brisbane, Australia) will join with local

expert medical oncologists, radiation oncologists, pathologists, surgeons and interventional radiologists to present a wide-ranging syllabus that will highlight the importance of high-quality clinical practice in IO. IO is a dynamic and ever-expanding profession, and practising interventional radiologists (IRs) must be up to date across a wide range of clinical and technical skills. These sessions will emphasise the need for interventional radiologists to assume responsibility

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for the clinical care of their patients, and to develop a pattern of practice similar to that of all other oncological disciplines. In turn, this will help IRs to take image-guided interventions into the “mainstream” of oncology.

Teaching will include overviews of tumour biology, pathology, treatment options, clinical algorithms and the critical role that IO has to play in the diagnosis and clinical management of cancer. Sessions will also focus on clinical skills relevant to IR, including

procedural sedation, post-procedure analgesia, how to establish and grow an IO clinic, and future IO research areas.

Unlike other IO workshops, the Clinical IO Symposium will not focus on expert technical explanations about how to perform procedures or “hands-on” displays. Instead, the symposium aims to educate IRs about how the IO techniques they perform fit into treatment algorithms, when they should be considered, and how to assess oncology patients.

Kenny, TROG Interventional Oncology Interest Group co-chair, said she was excited to participate in what is another world-first development involving interventional oncology and radiation oncology. “To the best of our knowledge, this is the first time that an IO workshop has been wholly dedicated to imparting purely clinical aspects of interventional oncology,” Kenny commented.

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Continued from previous page

an interventional radiologist performs a procedure is critically important, it is equally necessary for IRs to be able to assess patients clinically and to know when certain interventions are appropriate.

“I am thrilled that radiation oncology and interventional oncology, both using image-guided focal therapy, are coming together in this way. We have so much to learn from each other,” added Kenny.

Adam, a well-known advocate of interventional oncology in Australia and New Zealand, was impressed by the unique approach. “Interventional oncology can by practised safely only as a clinical discipline. If interventional oncologists do not assume primary clinical responsibility for the patients they treat, they cannot ensure optimal care and run the risk of errors. For example, if follow-up of patients undergoing percutaneous ablation is delegated to the referring physician, delays in the diagnosis of recurrent or residual tumour can occur, and potentially treatable disease can become untreatable.

Adam added: “Interventional

Interventional oncology oncology is already making a significant contribution to contemporary cancer care, but has enormous unrealised potential, which can be harnessed only by its practitioners becoming fully-fledged clinicians. Interventional oncologists should take pride not in their technical expertise, which should be assumed and taken for granted, but in being

Nicholas Brown

‘proper doctors’, like all other oncologists. This is the main value of this innovative workshop.”

“Interventional radiologists need good clinical training to support their technical skills,” said Nicholas Brown, overall symposium convenor, co-chair of the IO Interest Group and chair of the of the RANZCR Interventional Radiology Committee. “We hope that by emphasising the clinical aspects of interventional practice the workshop will help IRs to fulfil their role as clinicians, and develop IO into the mainstream.”

Susan Goode, TROG Cancer Research CEO, said her organisation was delighted to once again incorporate interventional oncology into its annual meeting and was excited about exploring the potential for further collaboration on education, training and research. “This will be the second year that IO has been integrated into the TROG Cancer Research programme, and based on the great response in 2018, next year is promising to be even more successful,” said Goode.

In a plenary address in the main scientific programme, Constantinos

Mapping the future of interventional oncology: “The time to study augmented reality is now” “I used to sneak away to the arcade at seven years old to play pacman and asteroids; my goal with augmented reality really is to prove my mother wrong when she told me not to play video games as they would never be useful,” Brad Wood, National Institutes of Health, Bethesda, USA, jests. He speaks to Interventional News about how an early interest in gaming and technology transformed into a vision for the future of interventional oncology, with augmented reality assisted procedures potentially improving patient outcomes.

Augmented reality (AR) is the superimposition of digital features into the real world— unlike virtual reality, which involves a completely simulated environment. In interventional oncology (IO), AR can be used to display subcutaneous anatomy on top of the patient’s skin. Here, Wood speaks of the pitfalls and promise of this technology, emphasising that an AR revolution is imminent.

What is the current status of augmented reality in the IO space?

Augmented reality is in the developmental phase, which is an exciting time because it has a lot of potential. The hard part now is figuring out exactly how it will be useful; proving a clinical utility is the next step. Several options are possible: from preprocedural planning to postoperative feedback. I envision AR making its first inroad in preprocedural planning, as it is easy to do and does not change the procedure at all. However, intraand postoperative uses would be more impactful, in my opinion. Intraoperatively, the interventionist could use AR technology to gain information about the procedure in real time when the patient is on the table. Information is power, and knowing when you have a needle or catheter in the correct location in a patient is the most valuable knowledge for me. After the procedure, AR could be used to monitor and verify your outcomes. For example, AR could be used to visualise a pre-treatment and post-treatment tumour side by side, enabling a three dimensional comparison.

With all the excitement surrounding AR today, do you think any aspects of the technology are over-hyped?

All cool ideas have the potential to be overhyped, and AR is no exception. The development of surgical robotics was partially driven by billboards and hype, and not strictly science. The perception that it is definitely better to be operated on by a robot than a human allowed the technology to proliferate and penetrate practices perhaps before all of the major questions had been answered concerning when to use them and when and how they help.

New technology always exists on a dynamic spectrum: it is a continuum between innovation on one side, and robust, evidence based medicine on the other. To quote Aldous Huxley: “Innovations are initially viewed as madness.” The introduction of new technologies is a dynamic process, and there will always be a tension between experimental technological change and market acceptance. The best window of opportunity to study AR is now,

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IRs need good clinical training to support their technical skills.

Sofocleous will outline the important role of interventional radiologists in modern oncology, and will explain how collaboration between oncological disciplines can benefit patients.

Interventional radiologists at any stage in their career are encouraged to attend and learn more about important concepts in clinical oncology for the modern interventional radiologist. This course is also highly recommended to registrars, fellows and interventional radiologists wanting to develop their practice in IO. The symposium is supported by an educational grant from Terumo Interventional Systems.

right at the beginning of its clinical use. We want to define when to use it, how it is going to add value, and when it is going to be cost effective. We are doing a clinical trial on the use of AR in biopsy for ablation, focusing on the monitoring and navigation of needles. We are also looking into software options, trying to figure out the practicalities of the technology: what it will look like in a clinical setting, when to use it during a procedure, where the information gaps are in current practice.

What hardware would you need for AR?

It all depends on what you are doing. Most work is focused on goggles, of which a number are currently commercially available. The goggles are tracked, so register where the physician is looking at all times, and images can be superimposed over the interventionists’ field of view. However, in my initial experience, I think it is going to be more useful to use a smartphone or tablet that interfaces directly with the CT console or workstation, so would be integrated as part of the workflow. We can then hijack the smartphone’s gyroscope and camera to visualise the anatomy below the skin without the need for goggles.

Outside of medicine, what can interventionists learn from other disciplines currently using AR?

Presently, we are taking technology developed for gaming and trying to apply it to a problem in IR or IO. There is a precedent for this: GPS and multiple modality navigation were both originally developed for purposes outside of the medical field. Nvidea hosts a video gaming meeting which traditionally has been a purely graphical congress focusing solely on gaming. Recently, though, it has expanded to include all sorts of exciting new technologies: artificial intelligence systems, autonomous driving vehicles, and a lot of medical applications, including augmented reality offerings. There is nothing wrong with borrowing technology from other disciplines; we just need to ensure that we have a plan for the use of AR in interventional radiology to maximise its potential within the space.

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Artificial intelligence

Artificial intelligence will support clinical decisionmaking in interventional oncology Aaron Abajian Julius Chapiro Comment & Analysis Aaron Abajian and Julius Chapiro, New Haven, USA, write about results from an early experiment in applying artificial intelligence (AI) and machine learning as a decision support system in interventional oncology to illustrate its potential to overcome rigid staging and scoring systems in the locoregional treatment of liver cancer.

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ost patients with hepatocellular carcinoma (HCC) are diagnosed at intermediate to advanced stages of the disease and are no longer amenable to curative surgical or image-guided ablative therapies. In such cases, transarterial chemoembolization (TACE) is the only locoregional therapy that is fully endorsed by guidelines and therapeutic recommendations, such as the most recently updated Barcelona Clinic Liver Cancer (BCLC) staging system by the European Association for the Study of the Liver (EASL).1 Prognostication for therapeutic outcomes in HCC is mostly based on established clinical, laboratory and imaging data points. For practical reasons, such features are mostly organised in scoring systems to help guide therapeutic decisions. As an example, the model for end-stage

Pugh=bilirubin, albumin, INR, ascites, encephalopathy). In order to arrive at a therapeutic recommendation, individual scoring systems are often combined with clinical performance scores (such as the ECOG performance status score) and imaging data on tumour size to build straightforward decision support algorithms, such as the BCLC staging system. While such prognostication algorithms have introduced a certain level of standardisation for data collection, they are mostly based on statistically highly variable and cohort-dependent interpretation of retrospectively collected data. As such, there are currently more than 10 different, mostly regionally variable staging systems for HCC, each with slightly different therapeutic recommendations. This circumstance, in and of itself, indicates that none of them is sufficient to provide

There is a growing need for more patient-centred and individualised care, and artificial intelligence solutions, specifically machine learning algorithms, may help make sense of the potentially nonsensical. liver disease (MELD) score, and the Child-Pugh classification are commonly used to guide therapeutic decisions, transplant listing as well as to predict long-term outcomes following any intervention. 2 Most such scoring systems are based on a regression of basic laboratory or clinical parameters (e.g., MELD=dialysis status, creatinine, bilirubin, INR, and sodium; Child-

universally applicable answers for therapeutic decisions. Instead, most such systems merely group patients into rough categories, in some cases mixing highly heterogeneous patient groups into one class with similar treatment recommendations.

Interestingly, the recently published BRIDGE study, a global survey on patterns of management and treatment of liver cancer, demonstrated a

rampant non-adherence to guidelines across the globe. 3 In addition, modern clinical patient work-up generates an overwhelming, practically indigestible amount of disparate data such as laboratory and imaging parameters, which adds to the institutional and individual variabilities of multidisciplinary decision-making.

There is a growing need for more patient-centred and individualised care, and artificial intelligence solutions, specifically machine learning algorithms, may help make sense of the potentially nonsensical.

Along the lines of our National Institutes of Health (NIH)-funded effort to introduce more quantitative and data-driven solutions for locoregional therapy of liver cancer, we experimented with the idea of a specific statistical application in machine learning to predict outcomes after TACE before the actual procedure.4 As such, we used AI/machine learning techniques to predict an outcome using observed baseline features. Our study included 36 patients with HCC treated with TACE. We used 25 individual features, including lab parameters, clinical performance scores and 3D quantitative imaging biomarkers for tumour enhancement (qEASL values) to train logistic regression (LR) and random forest (RF) models to predict patients as treatment responders or non-responders. The performance of each model was validated using a so called “leave-one-out” crossvalidation where the entire dataset except for one patient is repeatedly used to confirm the applicability of the model to each patient. As a result, our models successfully predicted tumour response with an overall accuracy of 78% (sensitivity 62.5%, specificity 82.1%, positive predictive value 50%, negative predictive value 88.5%). The presence of cirrhosis, high volumes of contrast-enhancing, presumably viable tumour tissue on baseline MR imaging were among the strongest individual predictors. In addition, therapy with Lipiodol (Guerbet) rather than drugeluting beads was associated with a higher response rate.

Our model had several limitations, including, among others, the small cohort size and only a limited set of features that were initially considered for the model. However, this early experiment in applying machine learning as a decision support system in interventional oncology illustrates the potential of such methodologies to overcome rigid staging and scoring systems. Ultimately, if trained on larger datasets, such systems may introduce an element of personalised care where current approaches show gaps.

AI could help overcome disadvantages of staging systems

The obvious disadvantage of currently available prognostication and staging systems is that simple models are limited in

the amount of information that they can capture. For instance, it is unreasonable to expect a five-component model like the Child-Pugh to have a high accuracy in predicting the benefit of a complex and multifactorial outcome, such as tumour response to TACE. Tumour board participants routinely consider hundreds of pieces of information before arriving at a therapeutic decision which is ultimately based on their learned professional experience, having seen thousands of cases as a reference.

An ideal model would therefore take all patient-centred data as input to predict response to TACE or any other therapy, after being trained on a vast number of previously treated patients with a similar condition.

In the future, neural networks will be capable of incorporating much larger numbers of features and extract predictive patterns from data that were previously invisible. However, we are not quite there yet. In order to train an algorithm to “think” like a tumour board member, it must be exposed to thousands of datasets to learn from.

Interventional oncology has been practiced for almost a generation, and while individual clinical trials continue to be mostly underpowered, vast training data is available already.

Our next step as a community of interventional oncologists should therefore be to organise, collect and store a well-characterised multiinstitutional database which would enable us to introduce and study advanced machine learning based solutions to improve clinical decision making. Similar examples, such as the united network for organ sharing (in short UNOS) database exist and may inspire us to pool the resources necessary for success. Only then will artificial intelligence truly be given a chance to add value to the way we practice interventional oncology.

References 1 European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: Easl clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2018.

2 Asrani SK, Kamath PS: Model for end-stage liver disease score and meld exceptions: 15 years later. Hepatol Int 2015;9:346–54.

3 Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M: Global patterns of hepatocellular carcinoma management from diagnosis to death: The bridge study. Liver Int 2015;35:2155–66.

4 Abajian A, Murali N, Savic LJ, et al: Predicting treatment response to intra-arterial therapies for hepatocellular carcinoma with the use of supervised machine learning-an artificial intelligence concept. J Vasc Interv Radiol 2018;29:850–7 e851.

Aaron Abajian is a diagnostic radiology resident at the Department of Radiology, University of Washington.

He has no disclosures pertaining to this article.

Julius Chapiro is research faculty and interventional radiology resident, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, USA. He has received research grant support from Philips Healthcare, Boston Scientific, Guerbet, Rolf W Günther Foundation, German-Israeli Foundation for Scientific Research and is a consultant to Guerbet, Eisai and Philips.

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Phase III RCTs needed to prove radiofrequency ablation is effective against colon liver metastases Interventional radiologists must become involved in the multidisciplinary development of phase III randomised controlled trials (RCTs) to further assess the role of radiofrequency ablation in treating colorectal liver metastases. This view was expressed by Gianpaolo Carrafiello (Department of Diagnostic and Interventional Radiology, University of Milan, Italy), when he addressed the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) at the annual congress (22–25 September, Lisbon, Portugal).

SPEAKING AT A focus session outlining the lessons from the CLOCC (Chemotherapy and local ablation versus chemotherapy) trial, Carrafiello acknowledged that RCTs in interventional radiology are difficult to perform, but said they would help to persuade oncologists to work more closely with radiologists.

“We have many problems,” he says, elaborating: “the first one is that many of our procedures are operator dependent. The second one is we use different devices, and also the strategy is not always the same. And, we use different modalities of guidance, so maybe there are too many biases.”

Worldwide, one million people are diagnosed annually with colorectal cancer, up to 50% of whom will develop liver metastases. Only 10 to 15% will be able to undergo surgery, with five-year survival rates between 31% and 58% in carefully selected patients. For non-resectable disease, the

standard treatment is systemic therapy, prolonging survival for about two years.

Radiofrequency ablation (RFA) has been used to clear tumours from the liver, either alone or in combination with resection, but data on efficacy and survival were lacking until 2012, when the first results from the CLOCC trial became available. Longer-term findings were reported in 2017, and as a result, said Carrafiello, “radiofrequency is considered from ESMO (the European Society for Medical Oncology), in addition to surgery, to eradicate visible metastases in liver sites”.

CLOCC was a phase II study of patients with unresectable colorectal liver metastases (CLM), randomised between RFA (with or without surgical resection) plus adjuvant systemic therapy (FOLFOX with or without bevacizumab) versus systemic therapy alone (FOLFOX with or without bevacizumab).

The trial was performed in 22 centres in Europe where 119 patients

Interventional radiologists must become involved in the multidisciplinary development of phase III randomised controlled trials to assess the role of RFA in treating colorectal liver metastases.

were randomised; 60 patients to the experimental arm, and 59 to the control arm. The primary endpoint of the first study was a 30-month overall survival rate higher than 38% in the combined modality arm, with secondary endpoints progression free survival, overall survival rate, and health-related quality of life.

By 2017, patients in the combined modality arm had a statistically significantly longer overall survival than patients in the systemic treatment arm, with three-, five-, and eight-year overall survival rates at 56.9%, 43.1%, and 35.9%, compared to 55.2%, 30.3%, and 8.9% in the control group.

Progression free survival was statistically significantly prolonged in the combined modality arm as compared with the systemic treatment arm, with three-, five-, and eight-year rates of 27.7%, 24.2%, and 22.3 in the experimental group, against 11.9%, 5.9%, and 2% in the systemic treatment arm.

But the study’s findings are limited by the fact that it was originally designed as a phase III trial which was downsized to a randomised phase II trial due to a smaller than planned sample size.

Carrafiello said at CIRSE: “A larger sample size would have offered better protection against possible risks of imbalances between treatment arms, and better reassurance of the external validity of the results. And although the effect of RFA on progression free survival was significant, the effect on overall survival is still lacking.”

Lessons from randomised controlled trials utilising SIRT in liver cancer A recent session at CIRSE 2018 sought to go beyond the headline findings from a number of recent randomised controlled trials (RCTs) in interventional oncology to define the future research directions for selective internal radiation therapy (SIRT; also called radioembolization), particularly with regard to dosimetry and patient selection.

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ose Ignacio Bilbao (Clinica Universidad de Navarra, Pamplona, Spain), presenting on the SARAH (Sorafenib vs. radioembolization in advanced hepatocellular carcinoma) trial from France also compared it with data from the randomised controlled trial SIRveNIB (selective internal radiation therapy vs. sorafenib) study from Asia, that dealt with a similar research question.

The SARAH trial directly compared the efficacy of SIRT using yttrium-90 (Y-90) resin microspheres (Sirspheres, Sirtex) to sorafenib (Nexavar; Bayer). SIRveNIB compared the safety and efficacy of radioembolization and sorafenib in patients with locally advanced hepatocellular carcinoma. The primary endpoint of both trials was overall survival.

Results from SARAH showed that local treatments of SIRT did not lead to a planned superiority difference in overall survival, compared with standard-of-care systemic therapy with sorafenib. However, SIRT had far fewer side-effects and patients who received this treatment had a significantly better quality of life. Very similar data emerged from the SIRveNIB trial, which also failed to meet its primary endpoint.

“This has led to the most recent EASL Practice Guidelines (Journal of Hepatology, 2018) to recommend that radioembolization should not be used to treat hepatocellular carcinoma [in this setting], so this is not good news,” Bilbao said.

Looking more carefully at the data beyond the headline findings, Bilbao stated that in the per-protocol analysis of SARAH, 26.6% of patients did not receive the intended

Gianpaolo Carrafiello

Still, the legacy of CLOCC had been to enhance understanding of the combined treatment effects, Carrafiello said: “We have new technologies, we have new energy modalities of ablation, we have moved sometimes from radiofrequency to microwaves, and we have new imaging guidance systems. And we can also improve the effects of systemic therapy.”

A new direction for RFA is use in combination with immunotherapy.

Carrafiello suggested two mechanisms that potentially have an impact on the efficacy of immunotherapy when used with radiofrequency: “There are mechanical changes in the tumour microenvironment and inflammatory mediated changes in immune-phenotypes.

And the use of PD-1 [programmed cell death protein 1] and PD-1 blockade can boost the radiofrequency ablation immune response against tumours.”

treatment of SIRT and 7.2% of patients did not receive sorafenib. Similarly, in SIRveNIB, 28.6% of patients did not get the intended treatment of SIRT and 9% of patients did not get sorafenib. “This is an important bias in my opinion,” Bilbao said, while also showing that there were some patients in the SARAH trial who were enrolled despite their poor condition. Others, he said, were also undertreated.

Despite these shortcomings, Bilbao described SARAH as “a very positive study” that has shown the benefits of SIRT in certain subgroups of patients such as those with under 25% tumour burden, good liver function as measured by ALBI grade and those that had greater than or equal to 100Gy tumour absorbed doses.

Pointing to what can be learned from the outcome of these trials, Bilbao stated that both SARAH and SIRveNIB had been designed to show the superiority of SIRT. “There is no information regarding non-inferiority of the therapy that can be gleaned from these studies,” he said.

Speaking in particular about the Technetium-99m macro-aggregated albumin scan and refined dosimetry, Bilbao asked: should a bad uptake exclude patients for Y-90 treatment? Is it useful just for the evaluation of lung shunting? How can the activity be accurately evaluated for a personalised treatment?

“SIRT has clear local efficacy with regard to tumour response, and progression within the liver. It should be indicated in locally advanced hepatocellular carcinoma with a better patient selection and treatment Continued on page 28

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Interview

Profile

Gerard Goh

President of the Interventional Radiology Society of Australasia (IRSA) and European Board of Interventional Radiology (EBIR) examiner for Australia and New Zealand, Gerard Goh emphasises the expanding transnational Interventional Radiology landscape, with “greater international collaboration” between major societies. Here, he speaks to Interventional News about how he knew he had found his calling in the “demanding yet rewarding” discipline of interventional radiology, the need to balance innovation with evidence-based clinical research, and how his passion for fast cars led to a stint as a Formula 1 doctor.

What initially attracted you to interventional ments and analysis. Even in Australia NICE guidance is radiology? often considered at government levels. Australia offers Throughout medical school and when I was a junior doctor I wanted to be a surgeon. I loved the technical aspects of procedural work and operations, and the way in which surgery offered patients life changing procedures. As a surgical registrar, I soon discovered that interventional radiology (IR) too offered patients many life changing procedures by using minimally invasive techniques whilst offering quicker recovery times and less morbidity than many surgical operations.

In addition, the rate at which innovation in IR was making leaps and bounds inspired me like no other specialty had before. At that moment I knew I had found my calling.

Today, what is it you enjoy most about interventional radiology?

Being able to make such a big difference in a patient’s life and sometimes offering lifesaving procedures gives me great satisfaction as an IR. When I see how patients and their families’ lives are changed by IR, even receiving a simple ‘thank you’ makes me feel proud that we can make such a lasting impact on so many people. I could not do any of this without the support of the great teams of radiographers, nurses and administration staff that I have worked with in both London and Melbourne and I am fortunate to have such great colleagues.

Have you had important mentors throughout your career? What have they taught you?

There have been several IRs who have been mentors to me.

Professor Michael Lee from Dublin helped start my journey in IR. Professor Lee not only taught me many of my skills in IR, but he also taught me the importance of being a clinician. Taking an active role in patient management and having a clinical presence in the wards was much more important than being just a ‘technician’ performing a procedure.

When I was a junior IR at St George’s Hospital, London, I was greatly influenced by my colleagues Anna-Maria Belli and Robert Morgan. Belli and Morgan taught me the importance of leadership, research, and teaching. Research and innovation is an important area in IR, as sound clinical research leads to better patient treatments and outcomes. Teaching IR at all levels from medical students, radiology registrars, IR fellows and even IR peers ensures that knowledge and experience is shared for the advancement of IR overall.

You have worked for most of your career in Australia, but spent four years in the UK. How does the Australian healthcare system compare with the UK healthcare system, in your experience?

Healthcare and IR in Australia and the UK are very similar in many ways, such as the disease processes (although there are many more kangaroo related injuries in Australia), the provision of universal healthcare, as well as the way that medicine is practiced. However, the systems are also different in many ways. A particular strength of the UK system is NICE (the National Institute for health and Care Excellence), for which I was an advisor. NICE provides national guidance and advice for healthcare by using evidence-based assess-

a supportive framework for early clinical and pre-clinical research. The ethics and governance processes for performing first in-human trials as well as early safety and efficacy trials are well established, which facilitates running this kind of research in Australia. It is exciting to be able to assess new technologies and devices and to see how these can offer solutions to challenges we have as IRs in treating patients.

We are also able to influence the development and direction of many of these devices and companies to improve the technology. We have been involved with several first inhuman trials as well as safety and efficacy trials, in addition to many other trials, here in Australia. In the UK there are more challenges to performing first in-human trials and early clinical research and although it is not impossible to do so, it is a much more involved process. An interesting observation is that when new technologies are ready for market release, they are often prioritised for approval for use in Europe and the USA, followed by larger countries such as China and Japan first, largely due to corporate sales and marketing strategies. It takes a while for many of these devices to become available in Australia so often a device we have conducted a first in-human trial takes many years before it is available for clinical use, even though we were the first to use it!

Could you explain your current research interests?

I am involved with quite a few different research projects being the head of Radiology Research at my hospital. We are currently heading and involved with several first in-human trials for which I am unable to disclose any details! We are involved with several commercial global studies in some spaces, such as drug coated balloons and inferior vena cava (IVC) filters to name a few. In addition, we have several investigator-initiated projects running that include pancreatic and prostate irreversible electroporation (IRE). We have also recently completed some studies on IVC filters, radiation protection, artificial intelligence in IR and education in IR that are currently being finalised for submission.

Could you describe a particularly memorable case?

I will always remember a minor procedure I performed on a female patient who happened to be a major international entertainment celebrity. The reason why this was so memorable was that although I was treating someone who was famous, escorted by a bodyguard and had to use an alias to avoid unwanted attention, in the IR lab all social barriers were broken down and we were doctor and patient.

Even though the procedure was relatively minor and was not a highly stressful life and death situation, at the end of the procedure she was very grateful, commented on how comfortable the experience was, and left with a big smile on her face. It made me realise that Interventional Radiology can make a big impact on anyone regardless if they are an ‘ordinary’ person or someone famous.

As President of the Interventional Radiology Society of Australasia (IRSA), what is your main goal for the society?

My main goal is to work towards recognition of IR as a

specialty or sub-specialty in Australia and New Zealand. In our region IR is a reasonably well established specialty amongst our peers; however, we still have much work to do to achieve national recognition similar to that in many other countries, such as in Europe, the USA, and Canada. There is much work to be done in this space and we are working with the Royal Australian and New Zealand College of Radiologists (RANZCR) to achieve this goal. This process will undoubtedly last longer than my term as IRSA president, however I hope that I can guide our society in the right direction towards achieving this goal.

One of the initiatives undertaken in 2014 was when IRSA adopted the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) European Board of Interventional Radiology (EBIR) as a certification of recognition of IR training and an international IR certification for our region. In conjunction with CIRSE and RANZCR, IRSA has held the EBIR exam in Australia and New Zealand annually for the last four years, and this partnership has always been strong. The Australian/New Zealand EBIR sitting is open to all candidates internationally with many candidates taking the exam here instead of in Europe. We have over 75 EBIR holders from Australia and New Zealand and this number continues to grow year by year. The EBIR has helped many IRs in our region show their skills and expertise in IR.

You are an Associate Editor for the Journal of Medical Imaging and Radiation Oncology and have been a peer reviewer for many other titles. What do you think makes a good research paper?

A good research paper is one that clearly defines an objective, has a robust methodological approach in investigating this objective, and follows with a thorough

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Interview national conferences or to gain hands on experience abroad.

This year APSCVIR invited delegates from SIR and CIRSE to be involved with the outreach programme for 2019.

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Outside of your own research, what is been the most interesting paper that you have seen in the last 12 months?

Although it feels like this was published a long time ago, the ATTRACT trial (pharmacomechnical catheter-directed thrombolysis for deep vein thrombosis) published in the New England Journal of Medicine in December 2017 was probably the most interesting paper I have read in the last year. I like papers that provoke discussion and challenge IRs to do further research. The ATTRACT trial has certainly had its share of controversy and discussion around the world, and many IRs are now looking towards further research in treating Ilio-femoral deep vein thrombosis and May Thurner lesion stenting.

In your opinion, what are the most exciting new developments in interventional radiology that we can expect in the next five to 10 years?

I believe that interventional oncology will continue to grow over the next decade and there will be many developments in both intra-arterial and percutaneous techniques.

The technologies will be refined and improved over time and larger scale clinical trials well help guide practice.

An area to keep an eye on is immunotherapy, as this is a promising area where modulating the immune system in combination with chemotherapy may help to increase the effectiveness of cancer treatment. This is battling cancer on a molecular level and I believe IR will have role to play in this by helping to deliver or administer treatments.

What is the biggest challenge in interventional radiology at the moment?

detailed critical analysis. Whilst novel research is always exciting, not all research needs to be completely novel, as one can always improve on existing research and expand knowledge. When submitting research to a journal it is always recommended to do some investigating about the journals one intends to submit to. You will be able gauge what kind of research papers a particular journal accepts and tailor your submission accordingly. For those who are new to research I recommend finding a mentor, as their guidance will be invaluable and they will be able to help you improve and build on your research capabilities.

How has the field changed since you started your career?

The most noticeable change I have seen is the greater international collaboration between international IR societies around the world. This helps facilitate the spread of knowledge and helps IRs network with one another across borders.

CIRSE continues to reach out to non-European IR societies, with many who have joined as group members, IRSA included. As mentioned earlier, IRSA is holding the EBIR in conjunction with CIRSE, offering candidates the chance to sit the exam outside of Europe: a prime example of international IR collaboration. The Society of Interventional Radiology (SIR) is also reaching out to international societies with international group affiliation. The Asia Pacific Society of Cardiovascular and Interventional Radiology (APSCVIR), for which I am an executive committee member, continues to mature as an organisation and has been running outreach programmes where IRs, from regions where IR is well established, travel at their own expense to countries with developing IR programmes (for example Myanmar) to teach IR techniques and share knowledge. This is helpful as not all IRs from these countries have the opportunity to attend inter-

The biggest challenge facing Interventional Radiology is to keep up in producing high quality robust clinical evidence for the procedures we perform whilst keeping up with the rapid pace of innovation. If innovation progresses too quickly without the proper research, then it creates many problems, such as inadvertently treating patients with techniques and therapies that may cause more harm than good as well as weaken the credibility of IR. Throughout my career there have been many technologies and innovations that seemed at the time to be revolutionary or evolutionary; however, the subsequent clinical trials have demonstrated that there has been little or no clinical benefit to patients. As we are such a dynamic and innovative specialty we need to be able to produce high quality research that keeps up with the pace of change of technology to ensure that we are able to practice the best medicine for the best interests of our patients.

What advice would you give to someone wishing to start their career in interventional radiology?

Interventional radiology is an exciting, demanding but highly rewarding specialty. IR training will give you a great breadth of knowledge across many different disciplines of medicine and surgery and often IRs will be able to offer treatment when there are little or no options left for patients.

An IR will never stop expanding their knowledge. IR allows you to embrace the rapid pace of innovation, but remember that good clinical research is what ensures patients receive the best treatment possible. Most importantly, a good IR needs to be a competent clinician and leader.

What are your interests outside of medicine?

I have a black belt in Kung Fu and was previously an instructor for around 16 years. I am currently learning Brazilian Jiu Jitsu. Fast cars are another passion of mine; I currently own a Mercedes AMG, used to do amateur car racing and am a big Formula 1 fan (at one stage I was a Formula 1 doctor). I love travel, having visited 39 countries so far, and I have an Instagram travel blog @funkytyper.

I also collect Japanese whisky, with my favourite whisky being 18-year-old Yamazaki.

Current appointments

2014–Present: Consultant interventional and diagnostic radiologist, The Alfred Hospital, Melbourne, Australia 2014–Present: Co-director of training, clinical director of Research, Radiology Research Department, The Alfred Hospital, Melbourne, Australia 2014–Present: Adjunct senior lecturer, Department of Surgery, Monash University, Melbourne, Australia

Current society positions (selected)

2017–19: President, Interventional Radiology Society of Australasia (IRSA) 2017–Present: Executive committee member, Asia Pacific Society of Cardiovascular and Interventional Radiology (APSCVIR) 2015–20: Council member, European Board of Interventional Radiology, Cardiovascular and Interventional Radiological Society of Europe (CIRSE)

Appointments (selected)

2010–14: Consultant interventional and diagnostic radiologist and head of Trauma Radiology, St George’s NHS Foundation Trust, London, UK 2012–14: Honorary senior lecturer and

Teacher, St George’s NHS

Foundation Trust, London,

UK 2009–10: Fellow and clinical lecturer in Interventional Radiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland

Awards, grants and prizes (selected)

2017: Alfred Health senior medical staff prize for Clinical/Public Health Research 2015: Outstanding service award, Cardiovascular and Interventional Radiology Journal (CVIR)

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Lessons from randomised controlled trials utilising SIRT in liver cancer Continued from page 25

optimisation. Refined dosimetry will have a role to play,” Bilbao concluded.

scenarios compared to randomised controlled trials,” Helmberger stated.

SIRFLOX, FOXFIRE and FOXFIRE Global trials

SORAMIC trial

Thomas Helmberger (Klinikum Bogenhausen, Munich, Germany) analysed the SIRFLOX, FOXFIRE and FOXFIRE Global trials.

“The combination of chemotherapy plus a biological agent is standard first-line therapy in colorectal cancer. The liver is the dominant target site for metastatic colorectal cancer and hepatic metastases are the main cause of tumour-related death. Radiotherapy is a potent therapy in cancer,” he said to explain the rationale behind the use of SIRT and the design of these trials.

The FOXFIRE, SIRFLOX and FOXFIRE Global randomised studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer with SIRT using yttrium-90 resin microspheres in patients with liver metastases. The combined analysis comprised data from the SIRFLOX study and data from FOXFIRE and FOXFIRE Global. However, data from the combined analysis showed that there was no statistically significant difference between the overall survival of patients who received SIRSpheres plus standard first-line chemotherapy and those who received chemotherapy alone.

Outlining some of the new questions that the analysis provoked, Helmberger asked: did the study protocol tend to promote the inclusion of patients with potential extrahepatic disease and potential progressive disease? Is reducing the hepatic tumour load by SIRT as liver-directed therapy also reducing extra hepatic progression? Is failure to improve overall progression-free survival really a failure of systemic chemotherapy since extrahepatic disease is targeted by this treatment? Is RECIST 1.1 systematically underestimating the therapeutic effects resulting in deterioration of results?

SIRFLOX is the largest randomised controlled trial in the world with a medical device in interventional oncology; it was wellconstructed and monitored; reflected an up-todate chemotherapy regimen—and included more than 1000 patients said Helmberger in outlining the strengths of the study.

Commenting on its weaknesses, Helmberger alluded to the unusually large number of patients who were at high-risk for poor outcomes in the SIRT arm (such as the nearly 36% of those who had extrahepatic metastases, or the over 50% who had the primary tumour in situ). In addition, there was also a significantly intensified systemic chemotherapy regimen in the non-SIRT arm that may have contributed to an imbalance treatment between the two arms of the trial which might have led to the control arm seeing better results, he pointed out.

“The impact of study design and patient stratification is crucial.

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Roberto Iezzi (Catholic University, Rome, Italy) presented on the phase II SORAMIC trial, a large investigator-initiated randomised controlled trial that evaluated sorafenib in combination with local microtherapies (either radiofrequency ablation in a curative group, or SIR-Spheres in a palliative group) for the treatment of unresectable hepatocellular carcinoma (HCC), and guided

by Primovist-enhanced magnetic resonance imaging (MRI). The primary endpoint of the curative arm was time to recurrence whereas for the palliative arm it was overall survival.

“SORAMIC combines the most promising novel diagnostic and therapeutic approaches in HCC treatment available to date: diagnosis with hepatocyte specific contrast agent Primovist; microtherapy with SIRT or radiofrequency ablation; and systemic treatment with tyrosinekinase inhibitor sorafenib,” Iezzi explained.

Results from the palliative group presented earlier this year revealed that SIRT in combination with sorafenib did not provide a significant survival benefit compared with sorafenib alone in patients with advanced hepatocellular carcinoma.

However, although the overall survival rates in the total patient population did not differ significantly between treatment groups, subgroup analyses suggested possible survival benefits with adding SIRT to sorafenib in some patient groups. It was these subgroups that Iezzi emphasised at CIRSE. “There was a survival benefit in younger patients, those with a non-alcoholic aetiology of the cirrhosis, and those with no cirrhosis at all,” he said.

Furthermore, this trial confirmed that the addition of SIRT to sorafenib is safe and feasible with a toxicity similar to sorafenib alone. Summing up, Iezzi pointed out that these results could justify and encourage the combination of SIRT with also other systemic anticancer treatments, such as immunotherapy. In particular, continuous tumour radiation delivered by SIRT may have immunomodulative effects so that, combined with immune checkpoint inhibition or T cell therapy, could potentially result in improved clinical outcomes.

Further, as this was a palliative study, there was no post-treatment imaging required and therefore, there was potentially no informations on tumour response, downstaging, total time to progression and progression-free survival, Iezzi noted. These parameters could demonstrate the superiority of combined group.

“My take-home message is that we have to perform really tailored treatments based on the indications and appropriate selection of patients. This trial highlighted that liver function clearly is the key. The evaluation of SORAMIC data is still ongoing so this is a continuing discussion,” he said.

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Intravascular imaging

Leap: The tiny camera that will disrupt intravascular imaging A single-use, high-definition miniature camera has been hailed as a “breakthrough innovation” in intravascular surgery, as Cambridge Consultants announced the device’s launch. Called Leap, the technology allows a digital view inside veins and arteries for the first time.

LEAP BUILDS ON the latest generation of sub-millimetre cameras, enabling surgeons to visualise parts of the anatomy that are currently inaccessible with today’s imaging techniques. With the potential for even smaller cameras on the horizon, this highly miniaturised ‘chip-on-tip’ architecture features a 400x400 pixel image—0.16 megapixels as a standard capability—an order of magnitude improvement over standard fibre-optic angioscopes. Chip-on-tip refers to the location of the imaging sensor at the distal end of the endoscope, in contrast to traditional fibre bundles which transmit light to large, external processing towers.

According to a press release, in the future, Leap technology could be combined with Cambridge Consultants’ ‘super-resolution’ image processing to increase the resolution further to 1600x1600 pixels (2.6 megapixels). This state-of-the-art proprietary technique harnesses deep learning to enhance low resolution images without the blurring associated with traditional upscaling and will ultimately provide visualisation for the most challenging cardiovascular surgery, the company claim.

Despite the ability to provide unique predictive information, current surgical endoscopes are not widely used in angioscopy due to poor flexibility, a limited field of view, and low resolution.

At 1.35mm in diameter, the Leap early prototype can be used in a procedure such as intracoronary angioscopy. Leap increases the information available to surgeons with new functionality, such as enabling tissue classification or direct imaging of non-standard vascular occlusions. Moving beyond the traditional endoscope, inspection with a Leap device could be paired with

today’s leading technologies, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), enabling enhanced diagnostic techniques during surgery.

Cambridge Consultants say that while existing endoscopes carry an elevated risk of infection and device damage due to inadequate sterilisation between procedures, a single-use endoscope Leap can be operated from a standard computer, so is not reliant on the availability of large and expensive operating room infrastructure. The falling costs of chip-on-tip technology means that the expense associated with traditional endoscope systems is set to significantly reduce. This is achieved with the introduction of an economical, reposable device, removing the need for sterilisation and maintenance.

“We have combined our intravascular device experience with our knowledge of microoptics, systems engineering and artificial intelligence, in conjunction with external manufacturing partners.

The result is an economically viable, disposable camera system that is small enough to fit into the working channel of a typical vascular catheter,” says Simon Karger, head of Surgical and Interventional Products at Cambridge Consultants. “For the first time, Leap offers practical, direct visualisation in the procedure room and a platform for integration of new configurations, sensor types and imaging modalities (such as spectroscopy). This can enable a new level of advanced imaging in intravascular procedures and an unparalleled surgical experience” he adds.

Leap was showcased at the Asia Pacific MedTech Forum 2018 (9–10 October, Singapore).

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Diversity in IR is crucial to harnessing the best ideas and innovations Daniel Sze (Stanford, USA) tells Interventional News that the focus on diversity is not just about social justice. “It is really about bringing the many good ideas and innovations that will come from women and underrepresented minorities to the table in order to advance the field of interventional radiology,” he said at the 2018 annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 22–25 September, Lisbon, Portugal). Sze is also the programme chair for the Society of Interventional Radiology annual scientific meeting that will take place in March 2019 in Austin, Texas.

Why is diversity in interventional radiology important?

The membership of the Society of Interventional Radiology, as well as of CIRSE, is only about 9% women, and actually fewer than that of underrepresented minorities, although we do not have the exact numbers.

Even though the field of interventional radiology has made great progress in 50 years, it has been mostly due to the contributions of men; mostly Caucasian and Asian. Going forward, our field now has its own training programme, the IR/ DR pathway, and what we are already seeing is that our field is attracting people who in the past were underrepresented, including women, and underrepresented minorities. This is great news for our field, because everyone can have good ideas that can contribute to the progress of interventional radiology. Up until now, many of these people have not been represented in this field, and have not had the opportunity to contribute.

One argument that I make in favour

of diversity and inclusion is that it goes beyond social justice. I am interested in gathering as many good ideas and innovations as possible, many of which will come from women and underrepresented minorities who do not have a seat at our table. That is who I want to exploit! I want their input to help our field.

What changes are helping foster a diverse workforce?

The main change that has happened in the field of interventional radiology, which has happened only in the last few years, is that, rather than being a sub-speciality fellowship that people take after five years of internship and diagnostic radiology residency, we now have our own IR/DR pathway. So instead of recruiting people from the diagnostic radiology pool, we are now recruiting people from the medical student pool.

Instead of competing against other diagnostic radiology specialties, such as mammography, and neuroradiology, and muscular-skeletal, we are now

Daniel Sze

competing against other sub-specialties in surgery, for instance general surgery, neurosurgery, cardiac surgery, to attract qualified and interested medical students into our field. So it is a completely different pool from which we are fishing.

Observation of role models is crucial…

We all know about the importance of role models in the development of careers,

from students, trainees, people who are just entering the field. The fact that our role models that are available today are not very diverse can actually have a negative impact on the recruitment of people coming into our field. We need to show the medical students that are considering a career in interventional radiology, that there are people in IR, whether they are male or female, whether they are Caucasian or Asian or an underrepresented minority, that there is a great interest in improving the diversity of the field of interventional radiology.

The key message here is that interventional radiology is changing.

It is changing rapidly. In large part, this is because our training programme is now separate from diagnostic radiology. Because of that, we are recruiting a different type of student to enter the field of interventional radiology. We have already observed improvements in the recruitment of women, and of underrepresented minorities, and this will change the face of interventional radiology.

A “mediocre success rate” found for coil embolization to obtain intrahepatic redistribution in radioembolization Coil embolization of hepatic arteries to induce redistribution of blood flow and microspheres has a mediocre success rate, concluded a recent study presented by Ahmed Alsultan (University Medical Center, Utrecht, the Netherlands) at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting (22–25 September, Lisbon, Portugal). The data further led Alsultan to advise physicians—when dose planning for a patient—to take into account that the radiation dose in the dependent regions is lower in general.

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lsultan acknowledged that variations in hepatic vasculature can pose a problem for patients undergoing radioembolization. Such variations may require one or more extra injection locations for radioembolization. Yet, according to Alsultan, redistributing the flow by coil-embolizing the problematic artery may be a way of overcoming this issue; eliminating the need for extra injection locations. Therefore, preexisting intrahepatic collaterals would be expected to take over the distribution of blood to a particular area, although Alsultan reported that in practice, himself and his colleagues have observed mixed results.

This led the investigators to carry out a retrospective study in order to screen all radioembolization patients in their affiliated institute, including patients that had a closure of the tumour-feeding artery. By doing so, Alsultan and colleagues aimed to evaluate the effect of coil-embolization of tumour-feeding vessels on the redistribution of blood flow in radioembolization.

To visually assess the effect of redistribution of the microspheres, post-therapy nuclear medicine images were taken from the PET (positron emission tomography) scans—subsequently analysed by two nuclear medicine physicians. The effect of redistribution was quantified by comparing the relative dose to the coil-embolized (dependent) segment relative to the other (non-dependent) segments and to the tumour in that segment on posttreatment PET and SPECT (single photon emission

Ahmed Alsultan

computerised tomography) scans using Simplicit90Y (Mirada Medical) software.

Alsultan pointed to a particular case: a segment four artery that could not be targeted with an injection to the left hepatic artery. The investigators decided to coil this artery and to inject the microspheres proximally to those in the left hepatic artery. According to Alsultan, the nuclear medicine image displayed very good redistribution of the blood flow, while the dosimetry data showed promising ratios: the segment ratio being 1.88 and the tumour ratio 1.21; indicative of good redistribution.

However, he noted that in other instances, less promising outcomes were observed. He discussed another case of a phrenic artery (that supplied three tumours) that

was also coiled. Yet in this case, the nuclear medicine image from the PET scan depicted poor distribution and very low tumour rates (segment ratio of 0.93, tumour ratio 0.33).

Of the 37 cases in total, 32 were available for dosimetric analysis and 35 for visual analysis. Regarding the visual analysis, Alsultan reported that around 70% of patients had good redistribution of blood flow (with good interrater agreement, kappa=0.82).

To determine the level of blood redistribution, Alsultan and colleagues came up with three cut-off values: 0.9, 0.8 and 0.7, that correspond to a decrease in the absorbed dose of ten, 20 and 30 per cent, respectively. Therefore, a 30% success rate was observed for the 0.9 cut-off values, and a 55% success rate was observed for the more “liberal” cut-off value of 0.7.

In terms of the segment analysis, the success rate ranged from 46–69%. The median ratios of the dose to the dependent segment and the non-dependent segments were 0.88 (range 0.26 – 2.05) and 0.79 (range 0.19 – 1.62) for dependent tumours compared with non-dependent tumours.

In light of these data, Alsultan concluded that coil embolization of hepatic arteries can be used to redistribute the blood flow and the microspheres. However, he stressed that physicians should keep in mind that the radiation dose in the dependent region is lower in general, which should be taken into account when dose planning.

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Radiation protection

Essential radiation protection for the modern interventionalist reduction effect is highly dependent on the size of the gutters between the protective glass and the skin.

Therefore, protective glasses should be tailored to each operator, with close fit and large protection area.

Kevin Mani

Additional risk and options

Comment & Analysis Addressing the importance of radiation protection for the modern interventionist, Kevin Mani writes about the need for knowledge and training in radiation protection for vascular surgeons and interventionalists, and radiation protection as an integrated part of training.

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he majority of vascular surgical procedures are today performed with endovascular techniques. The massive increase in the number of endovascular procedures, as well as the increasing complexity of these procedures, necessitates that specific attention is paid to the risks associated with radiation exposure in relation to endovascular surgery. The repetitive exposure of modern interventionists to high radiation doses is of major concern. Several pioneers in the vascular surgeoninterventionalist community have paid a high price for the developments made in endovascular surgery during their time in practice due to excessive radiation exposure, with development of radiation induced cataract as well as neoplasms. Although knowledge regarding the true risks with occupational radiation exposure is still scarce, recent studies indicate that measurable DNA damage among operators occurs already after a simple EVAR procedure.1 Additionally, there are indications of higher prevalence of left-sided brain tumours among physicians with occupational exposure to interventional radiation.

Strategies

Measures to reduce occupational radiation exposure during endovascular procedures are twofold: 1) reducing the radiation dose, and 2) applying adequate protection to reduce scatter radiation. Reduction of radiation dose adheres to the “as low as reasonably achievable” (ALARA) principle, which mandates medical use of X-rays to be limited to the lowest possible dose. In endovascular surgery, this is based on cautious and meticulous X-ray technique.

Measures to reduce radiation dose include application of adjusted low dose programmes with minimum pulse frequency and radiation energy which are tailored for the type of endovascular procedure being performed. Such targeted fluoroscopy and angiography algorithms can be developed together with interested hospital physicists in collaboration with the major providers of imaging equipment.

Adequate use of beam collimation, digital image magnification, 2D-3D fusion and image overlay are other methods proven to reduce the exposed field and required radiation.2 Reduction of the radiation dose has important benefits both for the patient as well as for the personnel. Real-time dosimeters used by the operating room personnel offers a possibility for direct feedback regarding radiation exposure, in order to increase awareness and modify behaviour.

Adequate protection

In addition to the reduction of radiation dose, use of adequate protection is key to reduce occupational radiation exposure during endovascular procedures.

Radiation protection measures can be classified into two groups: 1) radiation shields placed close to the patient, reducing scatter radiation from the patient in

Figure 1. The ZeroGravity radiation suite in use during a branched endovascular aortic repair at Uppsala University Hospital.

general, and 2) radiation protection placed close to or worn by the personnel. Ceiling suspended shields, table mounted shields and disposable radiationabsorbing surgical drapes such as RadPad all encompass radiation protection close to the patient.

A properly used combination of these shields can successfully reduce scatter radiation with >80%. The functionality of shields placed close to the patient is however highly dependent on adequate positioning of the shields. Challenges to correct use of these protective shields during complex endovascular surgery include collision of ceiling mounted shields and operating light or flat panel detector, lack of adequate shielding during lateral projection fluoroscopy/angiography, and lack of protection on the patient’s left side during interventions performed, e.g. from left brachial or axillary access.

Basic protective shielding for personnel includes the use of a lead apron and thyroid shield, complemented with protective glasses. Considering that the eye lens is the most radiation sensitive organ, eye protection should be a key element for all endovascular operators. Interestingly, experimental data suggest that the dose reduction effect of protective eye glasses varies significantly between different models, with the majority of the commercially available eye glasses offering a moderate 10–15% dose reduction at left eye. The dose

Even with standard lead apron and eye glasses, significant body areas including the arms, shins and head remain unprotected to scatter radiation, which may pose a risk especially for the primary operator closest to the source of scatter radiation. The landmark study by El Sayed et al showing radiation-induced DNA damage in EVAR operators could also verify that DNA damage can be reduced by additional use of radiation-protective shin guards. Optimal radiation protection would include protection for all exposed body areas. However, additional shielding may also be cumbersome and result in excessive weight, potentially with negative effects such as back pain and lumbar hernias. The suspended lead suit radiation protection system (ZeroGravity radiation suit) is an attempt to offer near to full radiation shielding without additional weight on the operator’s body. The system is based on a thick lead suit with a curved lead-acrylic head shield that is suspended either from a ceiling mounted monorail, repositionable floor unit, or a hinged swing arm. The ZeroGravity system offers excellent radiation protection for the primary operator, with significant reduction of the radiation exposure to the head, upper arms, and legs, in addition to what is today achieved with standard lead apron, Figure 1. In a recent assessment of the system in neuro-endovascular intervention, the suspended lead suit resulted in an additional 75% reduction in the operator-received total dose compared to standard protection including lead apron, glasses, ceiling and table-mounted shields.3 There is, however, still potential for further development. In our experience, the weight of the floor mounted ZeroGravity system may hinder repositioning possibilities. Additionally, a relatively high cost of acquiring the system may limit its use to high-volume endovascular centres.

Awareness

The increasing number of endovascular procedures in the field of vascular surgery is likely to continue in the future. This results in a need for knowledge and training in radiation protection for modern interventionists, and radiation protection is increasingly an integrated part of vascular surgical training. Although basic protection is achieved with adherence to the ALARA principle and the use of regular protective shields, the risk of repetitive occupational radiation exposure for interventionists remains a concern. Further innovation in endovascular surgery and radiation protection will play an important role in achieving the ultimate goal of zero radiation exposure during these procedures.

Kevin Mani is associate professor of vascular surgery at the Department of Surgical Sciences, Uppsala University, Uppsala, Sweden References: 1. El-Sayed T, Patel AS, Cho JS, Kelly JA, Ludwinski FE, Saha P, Lyons OT, Smith A, Modarai B, Guy’s and St Thomas’ Cardiovascular Research C. Radiation-Induced DNA Damage in Operators Performing Endovascular Aortic Repair. Circulation. 2017;136:2406-2416.

2. Hertault A, Maurel B, Midulla M, Bordier C, Desponds L, Saeed Kilani M, Sobocinski J and Haulon S. Editor’s Choice - Minimizing Radiation Exposure During Endovascular Procedures: Basic Knowledge, Literature Review, and Reporting Standards. Eur J Vasc Endovasc Surg. 2015;50:21-36.

3. Haussen DC, Van Der Bom IM and Nogueira RG. A prospective case control comparison of the ZeroGravity system versus a standard lead apron as radiation protection strategy in neuroendovascular procedures. Journal of neurointerventional surgery. 2016;8:1052-5.

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Act now to protect trainees and operators from radiation damage Senior staff in interventional radiology have a responsibility to better protect trainees from radiation damage during endovascular repair (EVAR) procedures.

THIS IS THE view of Bijan Modarai, professor of vascular surgery at King’s College, London, and Guys and St Thomas’s NHS Foundation Trust. He presented his findings on research into the effects of using lead leg shields to mitigate chronic exposure to low dose radiation at the London Aortic Symposium.

Afterwards, he spoke exclusively to Interventional News, and pointed out that there is “room for improvement” in how trainees are shielded from harmful effects: “The onus is on us, the deaneries and the trusts,” he said, “to make sure that we are fully protecting our trainees, and the same protective measures and protective items of clothing that are available to permanent consultant staff are also available to our trainees.”

In his talk, Modarai outlined the biological consequences of chronic low dose exposure for operators performing EVAR. “In 2018, we have realised that even though we sustain quite low doses of radiation, these are repeated exposures. And we have found evidence in operators of DNA damage in their circulating cells,” he explained.

The research focused on finding out whether there is an acute biological response in operators who are exposed to low dose radiation during X-ray guided endovascular procedures. Investigators isolated blood from operators immediately after a procedure and analysed it for markers of DNA damage in cells. They found that both the markers for cellular DNA damage and the repair process were raised.

The operators were tested again the following day and no markers were detected, “suggesting,” he said, “that there is an acute response”. But, he admitted: “What we don’t know is whether this repeated DNA damage– repair cycle that occurs in the operators’ irradiated cells leads to any genomic instability and an increased incidence of cancer.”

However, Modarai suggested that findings from previous studies indicate an associated risk although it is, as yet, unproven. Operators practising within radiology on a long-term basis, some for decades, were analysed for chromosomal aberrations — such as micronuclei and dicentrics which are markers of genomic instability — and an increased frequency occurred in those irradiated the longest.

He recommended the use of protective clothing to decrease exposure to radiation damage. “One of our key findings was that if you use leg shielding — i.e. use protective lead cover for your lower

half — it completely abrogated the DNA damage response. Our data show that it is key.”

Delegates attending Modarai’s

presentation at the symposium were surveyed to determine how many currently use leg lead shielding; it revealed a surprisingly low rate. “The vast majority said that they would rush out and buy leg lead, but only four were currently using it,” he explained, and called for greater action to optimally protect both operators and trainees.

“Permanent members of staff at each institution have the opportunity to ask for the protective items of clothing, and the protective equipment in theatre, to be instigated and used. Our trainees move from hospital to hospital each year and may not have that type of protection available to them as they move around.”

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Bijan Modarai

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Strategies needed to address high risk of radiation exposure during venous procedures Research presented at the European Society for Vascular Surgery’s annual meeting (ESVS; 25–28 September, Valencia, Spain) has shone a light on the potentially high cumulative radiation exposure associated with certain venous procedures. Addressing the issue, Stephen Black (Guy’s and St Thomas’ Hospital, London, UK) called for further studies to identify strategies to reduce radiation exposure and the need for increased awareness among interventionalists.

BLACK INDICATED THAT there has been an increase in treatment options for deep vein thrombosis (DVT) in particular and for chronic venous patients over the last few years.

While the advances are exciting, it is easy to forget that they come with potentially harmful side effects. Black compared modern venous procedures with endovascular aneurysm repair (EVAR), drawing particular attention to the young age at which venous patients typically require treatment, corresponding with a much longer lifetime of follow-up and potential reintervention procedures.

“It is important to highlight the potential for harm in this patient group who are an average age of 30–40 years, as opposed to the older patients who typically undergo EVAR, for example. The EVAR 1 trial reported an increased incidence of malignancy in patients treated endovascularly after 15 years follow-up. Patients who need thrombolysis or inferior vena cava (IVC) reconstruction are often younger than those with arterial problems and may also require long-term surveillance and secondary interventions, exposing them to further radiation,” Black pointed out.

To investigate the radiation exposure associated with venous procedures, Black and colleagues conducted a retrospective cohort study of patients with symptomatic ilio-femoral deep vein thrombosis and chronic IVC reconstruction, followed for a minimum of one year in order to capture reintervention data. Estimated radiation exposure from the related preoperative, index and postoperative interventions were measured in dose-area product and fluoroscopy time.

At St Thomas’s Hospital, Black explained that all procedures are performed in either the hybrid vascular theatre or in the angiosuites. Default background settings are used with a fluoroscopy pulse rate of 7.5/second in the hybrid operating theatre, 3.0/ second in the angiosuite and two frames per second for digital subtraction angiography acquisitions for all rooms.

The 39 patients enrolled in the study were a median age of 35 years (range=18–73) and 27 were male.

Nineteen patients were treated for lower extremity DVT and 20 for upper extremity DVT, and these two groups were looked at separately to observe any differences.

In terms of the configuration of stents for IVC reconstruction and the level of disease, three patients had unilateral iliac stents into the IVC, but the dominant group were either to

As interventionalists [...] we have to start getting out of these habits that expose not only ourselves but the patient to more radiation.

– Stephen Black the suprarenal component or a stent extension to the hepatic confluence.

The cumulative radiation exposure to patients undergoing IVC reconstruction was predictably higher, Black reported, with a mean dose-area product of 81,131Gy-cm2. Additionally, fluoroscopy time was long, with some procedures taking up to six hours. Level of radiation exposure also depended on the region which was stented.

“If we look at the difference between the two, it is clear that the stents that extended into the hepatic segment were associated with significantly more radiation exposure than those that remained below the infrarenal component. The cumulative radiation exposure, if we include all the followup, remains relatively similar in both the acute and chronic IVC stent extension patients. Further, we found that in patients with upper extremity DVT, the procedure was far quicker and therefore associated with far less radiation than lower extremity DVT. The same applies for cumulative dose-

area product and fluoroscopy time for all the reinterventions that occurred in the year after the initial procedure and the surveillance,” Black reported.

Comparing radiation dose measurements for IVC reconstruction with other vascular procedures, Black noted that it is significantly higher than lysis, for example, which has a median radiation exposure of 9Gycm2 and 981 seconds of fluoroscopy time compared with 60.8Gy-cm2 and 2,846 seconds for IVC. Compared to procedures such as EVAR and thoracic EVAR (TEVAR), however, the venous treatments do remain lower—especially complex procedures which have been associated with 287Gy-cm2 dose-area product and 4,152 seconds fluoroscopy time—but Black maintained that there should still be concern for the amount of radiation venous intervention patients are exposed to.

“This does not really change the story for venous patients. We can see that IVC reconstruction does have

a high dose of radiation exposure, with cumulative radiation over 40–50 years of a patient’s life really needing to be taken into account. The initial procedure for acute DVT is relatively low, but it is not insignificant, and these patients really are much younger than the arterial population and we need to be much more aggressive in reducing their exposure early on,” Black stated.

At his hospital, he said that they have moved to using magnetic resonance (MR) venogram instead of computed tomography (CT) scan in all of these patients for their initial work-ups, so as not to expose them to additional radiation dose. In particular, he added, the use of intravascular ultrasound (IVUS), helps to reduce radiation exposure in the form of contrast-enhanced runs, and is one of the main strategies he uses to reduce dose.

“As interventionalists, we have to learn that often we use another run as time to think about how to proceed, and we have to start getting out of these habits that expose not only ourselves but the patients to more radiation,” Black said.

He concluded, adding that more needs to be done to raise awareness about the importance of reducing radiation dose wherever possible, and maintained that more strategies, such as the use of IVUS, need to be identified and put into practice.

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Education

ADVERTORIAL

COVERATM Vascular Covered Stent for the treatment of venous anastomotic stenosis in dialysis access Panagiotis M Kitrou, consultant interventional radiologist, and Dimitrios Karnabatidis, professor of Interventional Radiology, both at Patras University Hospital, Patras, Greece, report on a case in which they successfully used a COVERATM Vascular Covered Stent (Bard, now BD) in combination with a high pressure balloon to treat two significant stenoses.

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62-year-old patient with a brachio-axillary arterio-venous graft (AVG) was referred from his dialysis center with signs of inadequate dialysis.

The patient’s venogram revealed a significant stenosis at the graft-vein anastomosis and a second stenosis just distal with presence of extensive venous-tributary network (Figure 1).

A 7mm diameter, 80mm length DORADO® High Pressure Balloon (BDPI, Tempe, Arizona, USA) was used to “beat” the stenosis. A flared 8mm diameter 80mm length COVERA™ Vascular Covered Stent was placed to cover both lesions. The final result is shown in Figure 2.

More than 50% of stenosis in AV Access Grafts present within 1cm around the venous anastomosis.1 Therefore, most new technologies have been tested and evaluated in this specific AV Graft segment. A study of paramount importance, published by Haskal et al in 2010, demonstrated a significant patency improvement over plain balloon angioplasty in both Access Circuit and Target Lesion when the FLAIR® Endovascular Stent Graft was used.2 Since then, several studies supported the above mentioned results showing consistency of data.3, 4 Until today, stent grafts are the only devices to provide significant patency improvement at six months compared to plain balloon angioplasty in multicentre randomized controlled trials.

The COVERA™ Vascular Covered Stent is used in our department for the treatment of venous-graft anastomotic stenosis. With our experience of more than 100 devices, the COVERA™ Covered Stent has proven to be an excellent

Figure 1: Stenosis (white arrow) at the anastomosis of a graft (black arrowhead) with a vein (white arrowhead) and a second stenosis (black arrow). Venous tributaries are filled with backflowing contrast medium (white stars). The wire in place can help separating the AVG from the venous tributaries.

Figure 2: COVERATM Vascular Covered Stent deployment at the site of stenosis (white arrow). The synthetic graft can now clearly be seen (black arrowhead) due to complete absence of venous tributaries.

and durable solution for the treatment of those resistant and frequently re-occurring lesions. Additionally, the ease of the deploying mechanism is an advantage because it can be controlled by fellows that have limited interventional experience. Data from the AVeVA study (prospective, multicentre, non-randomised, single-arm clinical study) showed a freedom from primary safety events rate of 96.4% and a six-month target lesion primary patency rate of 70.3% for the COVERA™ Covered Stent.

Our algorithmic approach suggests using a Covered Stent at the venous-anastomotic stenosis as a primary treatment in grafts older than 18 months and for patients with symptoms recurring within a short period of time (<3 months) after balloon angioplasty.

References 1. Kanterman RY, Vesely TM, Pilgram TK, Guy BW, Windus DW, Picus D. Dialysis access grafts: anatomic location of venous stenosis and results of angioplasty. Radiology. 1995;195(1):135-9.

2. Haskal ZJ, Trerotola S, Dolmatch B, Schuman E, Altman S, Mietling S, et al. Stent graft versus balloon angioplasty for failing dialysis-access grafts. The New England journal of medicine. 2010;362(6):494-503.

3. Haskal ZJ, Saad TF, Hoggard JG, Cooper RI, Lipkowitz GS, Gerges A, et al. Prospective, Randomized, Concurrently-Controlled Study of a Stent Graft versus Balloon Angioplasty for Treatment of Arteriovenous Access Graft Stenosis: 2-Year Results of the RENOVA Study. Journal of vascular and interventional radiology: JVIR. 2016;27(8):1105-14 e3.

4. Karnabatidis D, Kitrou P, Spiliopoulos S, Katsanos K, Diamantopoulos A, Christeas N, et al. Stent-grafts versus angioplasty and/or bare metal stents for failing arteriovenous grafts: a cross-over longitudinal study. Journal of nephrology. 2013;26(2):389-95.

The opinions and clinical experiences presented herein are for informational purposes only. The results from this case study may not be predictive for all patients. Individual results may vary depending on a variety of patient specific attributes. The physician has been compensated by BD for the time and effort in preparing the above case study for BD’s further use and distribution.

Why ISET 2019 is a must-attend meeting: Insight from a multidisciplinary slate of course directors For three decades, the International Symposium on Endovascular Therapy (ISET) has been providing clinicians with premier endovascular education. In 2019, ISET is investing in new programme enhancements to proactively address the growing need for highly specialised, interactive, and practical education for today’s endovascular and vascular specialists.

ISET’S HALLMARK LIVE cases, which showcase the practical application of cutting-edge endovascular techniques by top operators across the globe, will be expanded to include an additional 90 minutes of case time. Over 15 cases will transmit from several new sites across the USA and around the world, including: Houston Methodist Hospital (Houston, USA), Miami Cardiac & Vascular Institute (Miami, USA), University Hospital Leipzig (Leipzig, Germany), and Wellmont CVA Heart Institute (Johnson City, USA).

The programme will now feature dedicated tracks with interactive sessions woven throughout the course of the meeting, allowing attendees to customise their endovascular education. These tracks will be focused on critically relevant topics, including peripheral arterial disease (PAD), critical limb ischaemia (CLI), complex aortic and iliac interventions, clot management, venous interventions, and embolotherapy.

Late-breaking clinical data with a focus on promising new technologies will also be featured, along with the opportunity to earn 26.75 CME/CNE credits and gain invaluable insight from 70+ experts during 300+ lectures.

Messages from the ISET course directors

An expanded, multidisciplinary slate of distinguished course directors now guide the meeting’s programming and they cannot help but share their excitement for the enhanced programme. Several discuss why ISET 2019 is a must-attend meeting below:

Attendees gaining hands-on training at ISET

“ISET 2019 is interesting, novel, immediately relevant, and highly interactive. Join us for expanded clinical live cases at live case sites that offer the greatest amount of unbiased, multidisciplinary, practical teaching. Engage in dynamic town halls and late-breaking topic discussions every morning; then dive into one of our three focused tracks each afternoon,” enthuses interventional radiologist Constantino Peña (Miami, USA).

Vascular surgeon Daniel Clair (Columbia, USA), a new ISET course director for 2019, says: “ISET offers clinicians insight into a vast array of treatment methods used by multidisciplinary experts, supplying them with a broad armamentarium for dealing with patients. This year, “deeper dives” into areas of controversy and of particular interest to participants will provide them with heightened practical knowledge. I am honoured to be a part of a meeting that highlights collaboration, collegiality, and critical appraisal of care.”

Jihad Mustapha (Grand Rapids, USA), another new ISET

course director and an interventional cardiologist, comments: “The ISET faculty possesses deep knowledge of the very latest endovascular therapies. Working together, we help attendees from around the world leave the meeting confidently equipped with multiple solutions to complex obstacles they may face in daily practice. The education at ISET brings us closer to our common goal: better outcomes for our patients.”

Concurring with his colleagues, vascular surgeon Richard Neville (Washington DC, USA) adds, “ISET is an outstanding meeting that emphasises a multidisciplinary approach to vascular therapy in a collegial, but scientific, atmosphere.

There is a real cross-fertilisation of ideas and information that simply isn’t available at other meetings.”

Interventional cardiologist D Chris Metzger (Kingsport, USA) contributes his thoughts on the meeting: “ISET has been a longstanding leading forum for interdisciplinary vascular intervention education. It continues to evolve further by featuring current hot topics focused on changing landscapes and innovations and expanding live case venues worldwide.

This year promises to take ISET to new levels.”

Agreeing with his fellow ISET course directors, interventional radiologist James Benenati summaries: “Endovascular medicine is a fast-evolving field. Innovation is rapid and new technology developments are constant. ISET provides a fertile environment for multidisciplinary collaboration and sharing of research, innovation, techniques, and new ideas.”

Visit iset.org to learn more and register for ISET 2019.

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Oncology in politics

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SIR advocate for a reallocation of Capitol Hill funding to increase interventional oncologist numbers At the third Capitol Hill briefing from the Society of Interventional Radiology (SIR), Susan Sedory, executive director for SIR, along with a panel of experienced interventional radiologists, presented the case for interventional oncologists to become more involved with mainstream cancer treatment, emphasising the need to educate policy makers, financiers, and patients alike on the evolution of targeted cancer and pain medicine offering minimally invasive options. “The advent of these image-guided, organ-sparing procedures that are done through a tiny pin hole on the skin have changed the landscape of how we treat cancer,” summarised William Alago, panellist and interventional radiologist at Memorial Sloan Kettering Cancer Center, New York, USA.

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lago and Sedory, as well as fellow panel members David Prologo (Emory School of Medicine, Atlanta, USA), Alexander Kim, and Theresa Caridi (both Medstar Georgetown University Hospital, Washington, USA) advocated for increased Capitol support of interventional oncology as a discipline through breifing the audience on the Enhancing Opportunities for Medical Doctors Act. The bill, also known as HR 1167, was introduced to the House in 2017. According to Sedory, the bill looks to support three areas: new primary education in certain medical fields, of which interventional radiology is one; rural hospitals, which desperately need more physician opportunities to fill open positions, and hospitals associated with any brand new medical school. Of importance, Sedory stated that this bill does not seek to increase graduate medical education funding, but instead seeks the opportunity to reallocate unused money.

“As interventional radiologists, we are not having trouble filling our spots, in fact, we are over-subscribed.

What we want to do—instead of creating new spots—is to assign some of these unspecified positions to the new dedicated pathway trainees in interventional radiology”, Prologo explained.

Interventional oncology has “an identity issue”

The primary ambition of the SIR briefing—alluded to time and time again throughout the panel’s discussion— encompassed the issue of education: all five speakers agreed that there is currently a lack of knowledge regarding minimally invasive therapies, and patient access to these techniques is suffering as a result.

When Sedory questioned the panel on whether such minimally invasive treatments to cancer were available for everyone, Alago replied: “No, they are not unfortunately, and part of the mission of our society is to educate [the public] as well as our own referring oncologists about the effectiveness of some of these procedures. As we grow as a speciality, we have seen that more people are actually demanding these type of treatments because of their nature. At large academic centres it has been easier to get the message across so patients can access the care and options that are available; at smaller centres, it has been more of a struggle. I think as people become more aware, inevitably, the breadth and scope of our procedures will grow, and there will be more access for patients who need them.”

In agreement, Kim stated that patient access to interventional oncology procedures is the biggest limitation within this field of medicine today.

He commented: “The biggest barrier is patient’s understanding that interventional radiologists can provide therapy that could relieve them of their pain. We need to spread the word of other therapies available outside of the standard medical fields that people may be familiar with.”

Caridi alluded to a particular question that was raised at a previous SIR session: “If I am a patient, what should I ask when I go to my doctor?” She said that although the key phrase is “minimally invasive”, simply for the patient to understand that there is a less invasive option to surgery, and to ask accordingly, is half the battle.

In terms of patients on pain medication that are seeking other treatment options, Caridi said: “For a lot of patients, it is not about opioid addiction, it is the sideeffects that come alongside pain medication. Although

From left to right: William Alago, Theresa Caridi, Susan Sedory, Alexander Kim, and David Prologo at the third Capitol Hill briefing of the Society of Interventional Radiology

I am not doubting how miraculous they can be, opioids are known to cause severe constipation, and the patient is uncomfortable for other reasons. So, while pain medication can be very effective, it can be utilised in conjunction with what we do.” Certainly, in the context of the opioid epidemic, the panellists are in accordance that the sooner patients can stop taking pain medication, the better. Stressing the independence from opioids that minimally invasive procedures afford was one of their key messages, and one of the most persuasive arguments in terms of gaining audience approval.

The majority of patients have never heard of the minimally invasive therapeutic options that are available.

Summarising the issue of patient access and education concerning an awareness of interventional radiology, Kim said: “We have an identity issue. Unless you are a savvy patient who does a lot of internet research and can look into specific diseases and treatments, the majority of patients have never heard of the minimally invasive therapeutic options that are now available.

“The reason that this bill is so important is that it will allow us […] not only to increase the number of interventional radiologists in areas that are relatively under served, but also to have a bigger voice within medicine, giving people the opportunity to become more familiar with the therapeutic options that they have today,” Kim noted.

Minimal cost of interventional oncologic procedures an attractive argument for gaining potential financiers’ support

When questioned by an audience member on the costs of these minimally invasive procedures, Prologo explained two major areas in which interventional radiology most significantly affects cost. “The amount of money that we spend on inpatients […] can be extremely expensive, but we can save hundreds-of-thousands of dollars by

decreasing the pain to a manageable level in one short outpatient procedure,” said Prologo. Furthermore, as minimally-invasive therapies offer an alternative to surgery, he said: “We can cure someone of their cancer using a needle through a small puncture site that gets covered by a band aid—which is a lot cheaper than the pain medication, the potential complications, and the hospitalisations that can be associated with surgery.”

Speaking specifically about the beneficial economic impact of interventional radiology, Alago added: “In the advent of these procedures, people can get back to work, even some of the people that do heavier work, it is amazing.”

However, Caridi alluded to an example where the treatment option is not drastically less expensive compared to surgical options—the minimally invasive treatment of uterine fibroids. Irrespective of cost, she noted that an advantage of interventional techniques is that they remain patient-centred, as she stressed the importance of patient satisfaction regarding utilisation of the least invasive option available to a patient.

With regards to how interventional radiology has impacted the treatment of cancer specifically, Caridi described the array of minimally invasive techniques used today. She defined embolization for the audience—“essentially blocking the blood supply to the tumour”—and explained how it can be done by delivering chemotherapy directly to the tumour via small catheters in the blood stream, emphasising that it is a relatively pain free procedure. Further techniques mentioned included ablative therapies (usually with a curative intent), and irreversible electroporation.

“It is quite amazing, after 19 years of practice, I have seen the landscape transform itself into something that is so powerful and able to change the lives of cancer patients in a minimally invasive fashion,” enthused Alago of the evolution he has witnessed over his career.

Sedory concluded the briefing, highlighting that the society’s aim remains to spread awareness of this evolving medical field, and to educate patients on exactly what treatment options are available to them. However, she noted that the health systems are very supportive and understanding of the current array of minimally invasive therapies as they continue to evolve in a specialty that has been around for 50 years. Lastly, she stressed the importance of the bill: “Although the exact number of unspecified spots [able to be reallocated] is unknown, it remains around 1,300; a number that would certainly be impactful.”

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Innovation

BIBABriefings

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Strong investment in clinical trials is key for leadership in drug-elution

According to the Peripheral Usage and Attitudes Survey, physicians in Western Europe see strong investment in current and future clinical trials as the most important factor when considering which companies are the leaders in drug-elution technology (see Figure 1). Other important factors reported were having an expansive peripheral drug technology portfolio and providing clinical training/educational programmes.

Nobel prize for immunotherapy pioneers

The scientists—James P Allison and Tasuku Honjo—who developed the immunotherapy agents ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) have been jointly awarded the 2018 Nobel Prize in Physiology and Medicine.

Allison (University of Texas MD Anderson Cancer Center, Houston, USA) developed ipilimumab—now approved for use in Europe and the USA for the management of advanced melanoma— after realising inhibition of the T-cell protein CTLA-4 had potential as a treatment for cancer. Several scientists had observed that the protein worked as a “break” on T-cells and most focused on CTLA-4 as a target in the treatment of autoimmune disease.

However, Allison was unique in exploring its role in cancer—i.e. if inhibiting CTLA-4 could help the immune system to destroy cancers cells. Because of the benefits seen with ipilimumab in advanced melanoma, the agent is now being explored for use in other cancers such as nonsmall cell lung carcinoma and bladder cancer.

In parallel to Allison, Honjo (Kyoto University, Kyoto, Japan) discovered that the protein programme cell death 1 (PD-1) was expressed on T-cells and (similar to CTLA-4) acted as a break—if PD-1 binds to PD-1 ligand 1 (PD-L1), a T-cell becomes inactive.

Similarly, randomised controlled trial data were the most important driver in choice of device for managing superficial femoral artery lesions—whether the device was a bare metal stent, a drug-coated balloon, or a covered stent—and personal clinical experience was the second most important driver.

In terms of which company is perceived to be the leader in drug-elution technology, Medtronic was

the most frequently mentioned company (58 of 148 mentions overall; 39% of the sample) and Boston Scientific (31 of 148; 21%) was the second most frequently mentioned (see Figure 2). However, Boston Scientific was the most frequently mentioned company (36 of 147 mentions; 25%) and Medtronic was second (28 of 147; 19%) when asked which peripheral company came to “top of mind”.

Nivolumab, which is the product of work by Honjo and other researchers, is designed to prevent PD-1 from binding to PD-L1 (and thus allowing the immune system to attack cancer cells). It is now used to as a second-line treatment for metastatic melanoma (or as a first-line treatment in combination with ipilimumab in the absence of BRAF mutation), squamous non-small cell lung carcinoma, and renal cell carcinoma.

The chief clinician at Cancer Research UK, Charlie Swanton, told The Guardian that Allison and Honjo’s discoveries

Benefits of Credence BtK bioresorbable scaffold apparent at six months

Speaking at an innovation session at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), Gireesh Warawdekar (Holy Family Hospital, Mumbai, India) outlined the initial results for a novel belowthe-knee bioresorbable scaffold (Credence BtK, Meril). He reported that peripheral bioresorbable scaffolds had “intuitive promise” because they “leave nothing behind”, adding that the sirolimus-eluting Credence BtK scaffold was designed to degrade within two to three years. The scaffold has, Warawdekar commented, a PLLA strut thickness of 100μm, high vessel conformability, and optimal side-branch access.

An ongoing first-in-human study is exploring the safety and efficacy of the scaffold for the management of de novo lesions (length ≤56mm) in 30 patients

had had been transformational for understanding the potential of the human immune system to control or even eradicate cancers. He says: “A decade ago, metastatic melanoma was largely incurable. Thanks to work from Allison and Honjo, patients now have real hope, with over a third of patients deriving long-term benefit and even cures from such therapies.”

Image credit: © 2018 The Nobel Committee for Physiology or Medicine, Illustrator: Mattias Karlen

with critical limb ischaemia. The safety endpoints are the absence of complications at one-month post procedure and scaffold thrombosis as per the Academic Research Consortium (ARC) criteria at five years; the performance endpoints include technical success at 48 hours and clinical success at each follow-up, limb salvage rates at six and 12 months, and primary patency rates at one month and at one, two, three, four, and five years.

According to Warawdeker, there was no ischaemia-driven target lesion revascularisation, ischaemia-driven target vessel revascularisation or scaffold thrombosis at 30 days or six months.

However, there was one limb amputation.

“The benefit of this novel Credence BtK bioresorbable scaffold was apparent at 30 days and at six months where distinctive improvements in both Rutherford Class and the ankle-brachial index were observed in all patients,” he noted.

BIBA Briefings

BIBA Briefings is a new platform that provides in-depth analysis of the latest market intelligence from BIBA MedTech Insights, which provides consulting and market analysis services to medical professionals and organisations in the medical device industry in Europe and North America.

The aim of each report is to give an overview of the key information affecting the medical device industry, enabling those working in the industry to keep abreast of the latest developments and make knowledgeable decisions.

For more information about BIBA Briefings or BIBA MedTech Insights, please contact: sales@bibamedical.com

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Market watch

Product News Rivaroxaban gets FDA approval for treatment in CAD or PAD

Rivaroxaban, brand name Xarelto (Janssen), has received approval by the US Food and Drug Administration (FDA) to reduce the risk of major cardiovascular (CV) events, such as CV death, myocardial infarction and stroke, in people with chronic coronary or peripheral arterial disease (CAD/ PAD). Rivaroxaban is now the first and only Factor Xa inhibitor approved for patients living with these conditions.

This new indication is based on results from the landmark COMPASS

trial, which showed a significant 24% reduction of the risk of major CV events in patients with chronic CAD and/or PAD with a 2.5mg vascular dose of rivaroxaban twice daily plus aspirin 100mg once daily, compared to aspirin alone. This finding was driven by a 42% reduction in stroke, 22% reduction in CV death and 14% reduction in heart attack.

The risk of major bleeding was significantly higher in patients taking the rivaroxaban/aspirin regimen compared to aspirin alone, with no significant increase in fatal or intracranial bleeds.

“Despite the use of guidelinerecommended therapies, patients with chronic CAD and/or PAD remain at risk of having a devastating and irreversible CV event,” said Paul Burton, vice president, Medical Affairs, Internal Medicine, Janssen Scientific Affairs, LLC. “The new Xarelto vascular 2.5mg dose, when used with aspirin, represents a true breakthrough for patients with chronic CAD and PAD.” “Treating patients with aspirin only is simply not enough to address the underlying thrombotic risk that comes with chronic CAD and PAD,” said Kelley Branch, associate professor in Cardiology, University of Washington, Seattle, USA. “As we saw in the COMPASS trial, the dual pathway approach of aspirin and the 2.5mg, twice-daily dose of Xarelto can help significantly reduce the risk of CV events in these populations.”

Eximo Medical receives FDA clearance for B-Laser atherectomy system to

treat peripheral arterial disease

Eximo Medical has announced it has received 510(k) clearance from the US Food & Drug Administration (FDA) for its B-Laser atherectomy system for peripheral arterial disease (PAD).

B-Laser is a transformative 355nm wavelength laser technology designed to address unmet clinical needs for treating multiple vascular indications.

The specific indication cleared by the FDA is: “The B-Laser atherectomy system is intended for use in the treatment, including atherectomy, of infrainguinal stenoses and occlusion, including in-stent restenosis (ISR).”

“This clearance represents a significant milestone for Eximo, as we can now offer the B-Laser atherectomy system for PAD in the USA. This is the first 355nm laser system cleared in the Xarelto US for this purpose and, according to the clinical results and the feedback that we received from physicians, it seems that this wavelength provides significant advantages over traditional 308nm excimer lasers in term of safety, efficacy, cost and ease of use,” said Yoel Zabar, CEO of Eximo Medical. “We also plan to leverage our B-Laser platform technology to develop additional devices to address significant unmet needs in other vascular indications, including lead extraction (for which we have completed a proof of concept), coronary artery disease, thrombectomy and venous disease.

Additionally, we are developing an add-on diagnostic tool and disruptive medical device for interventional gastrointestinal procedures.”

Clinical evaluation of the B-Laser device in the intended population was performed in a prospective, single-arm, multicentre, open-label, non-randomised pilot clinical study in 50 subjects in Europe, as well as in a pivotal, prospective, singlearm, multicentre, open-label, nonrandomised IDE clinical study in 97 subjects in USA and Europe.

In the pilot clinical study, the results presented 100% success in crossing the target with no device related perioperative clinically significant adverse events and no complications requiring intervention.

There were no major adverse events (MAE) at one month or six months following the procedure, and only two cases (4.3%) of target lesion revascularisation among 46 subjects who completed the one-year post procedure follow-up. In the pivotal study, the safety and efficacy primary

endpoints were achieved with high margins and the six-month data was consistent with the pilot study results.

“I used the B-Laser in challenging procedures during the pivotal study and found the device easy to set up and use, and a valuable addition to our treatment portfolio,” said the national PI, John Rundback, interventional radiologist and director of the Interventional Institute at Holy Name Medical Centre, Teaneck, USA. “The enrolment in both US and Europe was quick (6.5 months), and the study results up to six months have been very impressive despite treating diverse lesions such as calcium, thrombus, and restenosis (including in-stent restenosis), both above and below the knee.”

BioMimics 3D stent receives US FDA premarket approval

UK-based Veryan Medical has announced that the company has received premarket approval (PMA) for their BioMimics 3D vascular stent system from the US Food & Drug Administration (FDA). The device is approved for the treatment of symptomatic de novo or restenotic lesions in the native superficial femoral artery and/or proximal popliteal artery.

The BioMimics 3D stent has a unique three-dimensional helical shape, designed to impart natural curvature to the diseased femoropopliteal artery, to promote swirling flow and elevate wall shear, which has a protective effect on the endothelium. Key components of the PMA application were the 12-month interim safety and effectiveness results from the company’s MIMICS-2 clinical study conducted under an FDA-approved Investigational Device Exemption (IDE) in patients with peripheral arterial disease undergoing endovascular intervention in the femoropopliteal artery. BioMimics 3D represents an innovative approach to the requirement for durable support for the arterial lumen after intervention. The helical centreline stent is designed to not only promote swirling blood flow but also to accommodate the complex biomechanical challenge associated with stenting this anatomically mobile artery.

The MIMICS-2 study enrolled 271 participants across 43 investigational sites in the USA, Japan and Germany.

The principal investigators are Timothy M Sullivan (Minneapolis, USA), Masato Nakamura (Tokyo, Japan) and Thomas Zeller (Bad Krozingen, Germany).

Both primary endpoints in the MIMICS-2 study, safety and effectiveness, were met. Freedom from major adverse events at 30 days was 99.6% (268/269) and Kaplan-Meier estimates of freedom from loss of primary patency and clinically-driven target lesion revascularisation were 83% and 88%, respectively, at 12-months; no stent fractures were detected in core laboratory imaging review.

Chas Taylor, Veryan’s chief executive officer commented: “We are

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delighted with the US FDA premarket approval, which is a major milestone for Veryan as we build towards global commercialisation of our BioMimics 3D Swirling Flow stent. I thank FDA for their invaluable support throughout the IDE/PMA process and applaud the hard work of all our staff in making this approval process so swift and straightforward.

The compelling MIMICS-2 results reinforce those from our earlier Mimics randomised clinical trial and the combined results support our belief that BioMimics 3D stands to become a first-choice nitinol stent for both primary and complementary stenting in the femoropopliteal artery.”

Retrospective study finds 97% success rate with Surfacer Inside-Out access catheter

Bluegrass Vascular’s Surfacer InsideOut Access Catheter System has demonstrated positive commercial use, consistently achieving central venous access in patients with upper body occlusions. A study presented in a poster session at the 2018 American Society of Nephrology (ASN) Annual Meeting (23–28 October, San Diego, USA) builds on positive results from the company’s post-market international SAVE Registry announced earlier this month.

The results of the retrospective, independent study evaluating 32 cases with the Surfacer System demonstrated an impressive 97% success rate in all patients. In one patient access was not achieved due to significant scoliosis altering the anatomy. There were zero devicerelated complications reported, including bleeding, haematoma and catheter-related infection, and all patients displayed similar catheter function at three months.

“The clinical application of the Surfacer System, as shown in this study, proves to be extremely positive,” states Roman ReindelSchwaighofer, Nephrology and Dialysis Fellow at the Medical University of Vienna in Austria and the lead author of the study. “The Surfacer System provides a safe and effective solution that both preserves and restores vascular access for patients requiring haemodialysis who otherwise have very limited options.”

The Surfacer System is a CEmarked device designed to reliably, safely and repeatedly gain central venous access for haemodialysis patients awaiting maturation of permanent vascular access. Failed venous access attempts may prevent permanent arteriovenous access, increasing patient morbidity and the overall cost of care.

“Based on these results, I am very optimistic about the clinical impact of the Surfacer System and its ability to treat upper body vascular occlusions,” states Gürkan Sengölge, associate professor of Medicine, Nephrology and Intensive Care Medicine at the Medical University of Vienna and the study’s senior author.

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Company news

Industry News BTG acquires Novate Medical

BTG has announced it has acquired Novate Medical, a medical device company focused on the prevention of pulmonary embolism in patients at high risk of venous thromboembolic events.

Novate has developed Sentry, the first bioconvertible inferior vena cava filter, which has recently been granted 510(k) regulatory clearance in the USA. Sentry’s 12-month clinical trial data demonstrated no new symptomatic pulmonary embolism and no evidence of device migration, tilt, fracture, perforation or embolization, complications which have been associated with some other inferior vena cava filters.

The unique bioconversion feature eliminates the need for an additional interventional procedure to retrieve the device.

BTG plans to launch Sentry in the USA in the second half of FY2018/19 and will sell the device through its existing vascular sales force.

“This bolt-on acquisition further enhances BTG’s strength in the vascular space.” says Louise Makin, BTG’s CEO. “Novate’s unique inferior vena cava filter offers our existing customers a highly complementary product in the management of pulmonary embolism.”

BTG paid US$20m in cash to acquire Novate and may be required to pay additional cash considerations up to US$130m if certain commercial and sales-related milestones are met.

Cook Medical announces successful resolution of 2014 FDA warning letter

Cook Medical has announced that it received a close-out letter from the US Food and Drug Administration (FDA) resolving a 2014 warning letter for processes related to the quality system at the company’s manufacturing facility in Bloomington (Indiana, USA). A company press release states that the resolution was a direct result of the company’s employees’ efforts to improve Cook Medical’s quality system over the last four years.

The 2014 letter issued by the FDA to Cook Medical stated that an inspection “revealed that your firm’s devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.”

“Receiving critical feedback from the FDA in 2014 was tough, but

beneficial. After a lot of thoughtful discussion, our leadership team decided this feedback was an opportunity to slow down and take a hard look at our company,” says Pete Yonkman, president of Cook Group and Cook Medical. “As a result, we established a plan to not only address the issues in the warning letter, but transform our entire company.”

A key part of that transformation was the recent realignment of the company’s business into two divisions, Vascular and MedSurg.

Other critical changes that are underway include improvements to accelerate the company’s product development process, to elevate the level of customer service, and to upgrade the company’s IT infrastructure. Cook also recently purchased a million-square-foot abandoned factory in Bloomington to provide room to redesign its manufacturing processes.

“As we have focused on resolving the warning letter and improving our company over the last four years, we have, at times, disappointed our customers. For example, adding new systems slowed our production capabilities, and we experienced shipment delays. We are not finished yet, but our teams have worked hard to improve our delivery times, and we thank our customers for sticking with us,” Yonkman continues.

“One of the benefits of being a family-owned, privately held company is that we were able to take the long view and invest in our company and our employees. We still have work to do, but we are proud of the progress our employees have made to get us to this important milestone.

Our transformation is making us a better, stronger company so that we can continue to fulfil our mission of improving the lives of patients around the world.”

Boston Scientific announces agreement to acquire Augmenix

Boston Scientific has announced that it has entered into a definitive agreement to acquire Augmenix, a privately-held company which has developed and commercialised the SpaceOAR system, a therapy used to reduce common and debilitating side effects that men may experience after receiving prostate cancer radiotherapy.

The transaction consists of an upfront cash payment of US$500 million, and up to US$100 million for reaching sales-based milestones.

Each year, more than 1.1 million men are diagnosed with prostate cancer worldwide and approximately 400,000 men will undergo prostate radiotherapy. One of the most common complications of treatment is rectal

radiation injury, due to the rectum’s proximity to the prostate and the resulting high doses of inadvertent radiation exposure. Prior to radiation therapy, the SpaceOAR hydrogel is injected to create additional space between the rectum and prostate during treatment, thereby reducing rectal radiation dose and associated

The SpaceOAR system

side effects.

The SpaceOAR hydrogel is CE marked, cleared by the FDA, and has been used in more than 30,000 patients worldwide. As a result of commercial adoption, expanded US reimbursement and a total addressable market valued at US$750 million, product sales are estimated to reach US$50 million in 2018, and approach US$90 million in 2019.

“The acquisition furthers our category leadership strategy in urology and the SpaceOAR hydrogel is a crucial addition to our growing prostate health treatment portfolio of products that improve the quality of life and clinical outcomes for men with prostate cancer and benign prostatic hyperplasia,” says Dave Pierce, president, MedSurg, Boston Scientific. “The injection of this hydrogel during a minimally-invasive, in-office procedure can reduce the unwanted and unintended side effects of prostate radiation and provide substantial peace of mind for patients and their treating physicians.”

Clinical trials in Europe and the USA have demonstrated that the space created by the hydrogel significantly reduces the amount of radiation delivered to the rectum. Additionally, the randomised SpaceOAR hydrogel US clinical trial demonstrated that patients who received the hydrogel spacer reported significantly less rectal pain during prostate radiotherapy and had significantly less severe long-term rectal complications, including zero incidence of grade 2 rectal toxicity versus a 5.7% rate experienced by patients without the spacer.

A single injection of the SpaceOAR hydrogel is designed to maintain the space between the rectum and prostate for three months—within the duration of a standard radiation treatment schedule. The absorbable hydrogel is gradually reabsorbed by the body within six months of injection.

“We are proud of the clinical and commercial outcomes we have been able to achieve for SpaceOAR hydrogel thus far, and are excited to drive accelerated adoption leveraging Boston Scientific’s urology and pelvic

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health expertise,” says John Pedersen, chief executive officer, Augmenix.

“The company also has the additional resources needed to further explore expansion of indication to other organs throughout the body that could benefit from space creation—such as gynaecological and pancreatic cancers.”

The transaction is expected to be immaterial to adjusted earnings per share in 2018 and 2019, accretive in 2020 and increasingly accretive thereafter. On a GAAP basis, the transaction is expected to be less accretive, or more dilutive as the case may be, due to amortisation expense and acquisition-related net charges. The acquisition is projected to close early in the fourth quarter of 2018, subject to customary closing conditions.

Guerbet announces appointment of Leeann Essai as North American head of marketing

Leeann Essai has joined Guerbet’s executive team as North American head of marketing.

In this role, Essai will report to Massimo Carrara, Guerbet vice president for North America, and will lead US and Canadian marketing for Guerbet’s diagnostic imaging offerings in contrast media, medical devices, and digital services, including the deployment of Contrast & Care and the Imalogix partnership. She will also be responsible for the development and execution of marketing strategy for Guerbet US in close collaboration with the company’s sales partners and internal stakeholders.

“We are delighted to welcome Leeann to our North America executive team,” comments Carrara.

“Leeann brings more than 20 years of global healthcare marketing and management experience to Guerbet.

Her deep healthcare IT knowledge makes her a valuable addition to our team in this exciting time of expanding our digital services offerings and continuing to increase Guerbet’s visibility and growth as a leading player in medical imaging worldwide.”

Essai joins Guerbet from Siemens Healthineers, where she was a global product marketing manager responsible for the worldwide product marketing of radiology imaging IT products in the digital health services portfolio. She also held successive roles of responsibility within Siemens Health Services. Prior to Siemens, Essai served in various marketing management roles at healthcare companies, including Cerner Corporation and MedQuist Inc. (now M*Modal), where she established that company’s marketing department and directed all external marketing efforts and internal communications.

Essai holds a Master of Business Administration from Pennsylvania State University, as well as a Bachelor of Arts in Journalism from the University of South Carolina.

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Clinical News US$60 million raised to fund sirolimus-coated balloon investigational trial

MagicTouch

Concept Medical has approached the FDA for an investigational device exemption (IDE) for their sirolimus-coated balloon (DCB). To support this process, they have raised US$60 million (for an undisclosed valuation) from cardiologist and serial entrepreneur Kiran Patel (Tampa, USA). An IDE will allow the device to be used in a clinical study to collect safety and effectiveness data.

The funds will also be utilised to augment clinical data and clinical registries to qualify for reimbursement in the European markets, where the company has commercially launched the product.

Concept Medical Inc. (CMI), headquartered in Florida, has a manufacturing subsidiary in India, by the name Envision Scientific Pvt. Ltd. (ESPL), where all their products are made. A portion of the funds will also be utilised to bolster the manufacturing operations to meet the increasing demand for their products globally. Their global distribution and marketing network are operated from offices in India, Singapore, the Netherlands and Brazil. ESPL also has an India-focused marketing and distribution business.

The companies (CMI and ESPL), which were established about 10 years ago, have developed innovative and disruptive platform technologies in drug-delivery systems to address the unmet medical needs in interventional cardiology. They have 96 patents granted (with another 40 currently in process) around the world.

The companies have previously commercialised their first product, Abluminus-DES coronary stent, which uses their proprietary drug delivery and coating systems. MagicTouchDEB, a sirolimus-coated balloon with application in coronary and peripheral arterial disease, is commercially sold in many European countries as well as South Africa, Mexico, Malaysia, Indonesia, Singapore, and in the MENA region.

Extended applications of MagicTouch-DEB in renal transplant, erectile dysfunction, and arteriovenous fistulae and grafts for renal dialysis patients are currently in on-going clinical trials.

CMI raised the funds from the family office of Kiran Patel and Pallavi Patel. With the fresh infusion of funds, both CMI and ESPL aim to bolster their operations in the existing and new markets.

Kiran Patel, a staunch supporter of innovative and disruptive medical technologies, says, “Cardiovascular diseases (CVDs) are the number one cause of death globally, representing 31% of all global death and it is increasing due to changes in lifestyle and increase in hypertension amongst the young and old. I am excited to be a part of CMI whose research and innovative technologies will meet a major unmet need in patients with diabetes and cardiovascular diseases.

This venture enables me to contribute to the millions of hearts beating around the world.”

SAVAL trial of new belowthe-knee drug-eluting stent begins

The first patient has been enrolled in the SAVAL pivotal trial to evaluate clinical outcomes of the SAVAL below-theknee (BTK) drug-eluting stent system (Boston Scientific) in patients with critical limb ischaemia (CLI). The SAVAL BTK stent system is the first CLI device to be recognised by the US Food and Drug Administration (FDA) Breakthrough Device programme.

Nearly 17 million people in the USA live with some form of peripheral arterial disease with 11% of these cases developing into CLI. Research has shown that within one year of being diagnosed with CLI, 30% of patients will have undergone amputation.

Arterial blockages below the knee can be challenging to treat effectively with traditional interventional procedures due to arterial recoil, which is the natural tendency of the vessels to maintain their original shape, and the high occurrence rates of calcified lesions.

According to Boston Scientific, the SAVAL BTK stent system is the first stent system designed specifically to address these anomalies with a paclitaxel-polymer combination to facilitate sustained release of an anti-restenotic drug proven to minimise tissue re-growth and vessel recoil, thus reducing the potential for revascularisation.

Due to the absence of effective treatment options for patients suffering from CLI, the FDA granted the Expedited Access Pathway (EAP) designation to the SAVAL BTK stent system. This programme is intended to provide patients timely access to medical devices that demonstrate the potential to address unmet clinical needs in treating life threatening or irreversibly debilitating diseases or conditions. In late 2017, EAP devices

were transitioned to the FDA’s Breakthrough Device programme.

“Critical limb ischaemia is a serious condition, affecting numerous patients at increasing rates across the globe,” said Jihad Mustapha, with the Advanced Cardiac & Vascular Amputation Prevention Centers in Grand Rapids, USA, and global principal investigator of the SAVAL trial.

“The commencement of the SAVAL Trial signals the advancement of endovascular techniques featuring the latest in drug-eluting stent technology, with the potential to drastically improve the quality of life for patients who live in fear of losing their legs due to CLI.” The SAVAL trial is a global, prospective, randomised, multicentre trial designed to assess the safety and efficacy of the SAVAL BTK stent system compared to percutaneous transluminal angioplasty (PTA) in treating patients with CLI. The study will include approximately 200 patients at 50 sites in the USA, Europe and Japan. First patient enrolment occurred at New Mexico Heart Institute in Albuquerque, USA by Steve Henao.

The SAVAL BTK stent system is an investigative device only. It is not approved for use or sale.

Merit significantly expands biopsy portfolio with release of new bone biopsy systems Merit Medical Systems has announced the expansion of its biopsy portfolio, with the release of five new manual bone biopsy systems. According to a company press release, each of

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lesions.

The patented perforating cannula included in the Madison and Huntington systems facilitates greater accuracy of placement through dense bone tissue. The stylet of these systems can easily be exchanged for a drill insert without losing the introducer cannula’s place in the bone; when used in conjunction with a drill, the edges of the perforating cannula simultaneously cut around the drill as the tip bores through the bone.

“The range of biopsy systems allows the physician to choose the needle best adapted to the bone density prior to or during the procedure,” says Jean-Denis Laredo, chief of the Radiology Service, Lariboisière Hôspital, and professor of Medicine at the Public Hospital of Paris, University of Paris-Diderot, France. “Having a Seldinger-inspired guide wire approach to the spine assists both experienced and younger radiologists in safely placing a larger needle. The biopsy is almost achieved once the introducer needle is against the target. This also provides a better anaesthetic for the patient, and less radiation caused by repeat scanning.”

In addition to the Madison and Huntington systems, Merit is also introducing the Madison Mini for small rounded bones that have little softtissue surroundings; the Westbrook, designed to reach superficial lesions in soft- or normal-density bone; and the Kensington bone biopsy system, which was created for deep bone, upper spine and narrow access procedures. The Kensington is used with the Seldinger-

Merit Medical biopsy devices

the systems has been specifically designed to optimise diagnostic yield in specialised settings, and, collectively, they provide multiple options for use in a wide variety of applications.

Featured in the new line-up are the Madison and Huntington bone biopsy systems. The direct access Madison features a trocar-tip stylet that can be introduced through the cannula to assist with initial bone entry. The cannula also supports the use of a drill insert that helps traverse hard bone for small cortical abnormalities in axial and appendicular cases. The Huntington is designed with a tri-angled tip and longitudinal groove that both maintains accuracy even in oblique approaches and functions as a collection channel for tissue evacuation upon first contact in hard bone procedures and sclerotic

inspired guide wire approach.

All of the systems utilise the Preston bone biopsy needle, which is constructed with clockwisecutting trephine teeth to support true cylindrical tissue retrieval and use even in sclerotic and blastic lesions. The systems also offer comfortable-grip handles that lock together to allow for more manual pressure if necessary, and depth stoppers to give a visual guide for biopsy needle protrusion beyond the introducer.

“The expansion of our biopsy portfolio allows us to better serve the needs of our customers and underscores Merit’s belief that offering a wide range of products gives practitioners a fuller set of options for instrument selection,” comments Fred Lampropoulos, chairman and CEO of Merit Medical.

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Market watch

Product News

ProVu

Acessa Health wins FDA nod for 3rd generation ProVu

Acessa Health has announced that the company has received US Food and Drug Administration (FDA) 510(k) clearance for its third generation Acessa ProVu radiofrequency ablation system intended for use in treating symptomatic uterine fibroids.

The company, based in Austin, USA, says the newly cleared system features ultrasound visualisation and a guidance mapping system, and that it is intended to provide a safe alternative to hysterectomy procedures for women suffering from uterine fibroids.

“The FDA clearance of Acessa ProVu is a significant step forward in terms of offering patients more minimally invasive options to address their fibroids,” former US Surgeon General Regina Benjamin comments in a press release.

“Acessa Health is delighted to usher in our next phase of innovation with the introduction of Acessa ProVu. Each phase of innovation—the original Acessa system, Acessa guidance system and now the Acessa ProVu system— represent a significant improvement in performance and the opportunity to further support our physician partners who help women suffering from uterine fibroid symptoms,” president and CEO Kim Rodriguez states.

In February, Acessa Health announced that 32 US state Medicaid programmes now provide access to the company’s Acessa procedure designed to treat uterine fibroids using radiofrequency ablation.

The FDA initially granted clearance to the first generation Accesa system in 2012, when it was a brand new medical technology used in the treatment of uterine fibroids. The announcement of this first market clearance was during the opening session of the Association of Gynecological Laparoscopists (AAGL) Global Congress on Minimally Invasive Gynecology.

cyanoacrylate liquid embolic agent.

Magic Glue is indicated for the embolization of arteriovenous malformations.

Magic Glue is a class III implantable medical device which is described as an arterial and venous embolization implant due to its haemostatic action, and is applicable in the fields of neuroradiology and interventional radiology. This medical device is applied in solution with a contrast agent.

“We are excited to enlarge our offer in the treatment of arteriovenous malformations with Magic Glue.

This cyanoacrylate glue offers new features compared to the historical glues on the market such as delayed polymerisation and less adhesion to the microcatheter. These characteristics will facilitate and expand cyanoacrylate indication in the neurovascular and peripheral fields,” says Nicolas Plowiecki, president of Balt.

“Balt is again expanding its embolization portfolio with a new cyanoacrylate solution that provides another treatment option for neurovascular and peripheral physicians. We were among the first to enter the arteriovenous malformations market with the Magic flow-dependent microcatheter. Thirty years later, BALT keeps on delivering innovative solutions for better patient treatments,” comments Pascal Girin, CEO of Balt and president of Balt International.

ICEfx cryoablation system launches globally at CIRSE 2018

BTG has announced the global launch of its ICEfx cryoablation system.

This is an evolution of the existing Visual ICE system, and according to Peter Pattison, head of Interventional Oncology at BTG, “offers predictable, reliable performance with seamless therapy delivery and exceptional ease of technical operation.”

ICEfx enables interventional radiologists to perform cryoablation procedures, facilitating precise and effective treatment without the need for surgery or repeated radiation treatments.

“The ICEfx cryoablation system is a new, more compact design that simplifies the procedure through a set

Balt announces receiving CE mark for Magic Glue, a next generation cyanoacrylate

Balt International has announced receiving the CE mark for Magic Glue, its next generation of

Magic Glue (Balt)

of user-friendly on-screen prompts,” explains interventional radiologist AJ Gunn (University of Alabama, Birmingham, USA). “It is easy for my technicians to set up, operate, and shut down. Importantly, this updated version is designed to work with the current line of BTG cryoablation probes, meaning that physicians can still create the reliable ablation zones they have come to expect.”

Pattison comments: “We continue to invest in both new product innovations and clinical research. Building on our commitment in interventional oncology (IO), BTG has added the most advanced cryoablation technology to its portfolio of minimally invasive therapies and is currently supporting a number of active clinical research studies in bone, kidney, lung, pain and prostate. We strive to provide healthcare professionals with easy access to innovative product choices, our BTG IO portfolio allows them to select and tailor each clinical solution to match a specific patient need.”

The ICEfx cryoablation system was launched at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) meeting (22–25 September, Lisbon, Portugal).

Cardiovascular Systems announces launch of Peripheral Orbital Atherectomy System outside the USA

Cardiovascular Systems Inc. (CSI), a medical device company developing and commercialising interventional treatment systems for patients with peripheral and coronary artery disease, has announced that the first patient in Hong Kong has been treated with its Stealth 360 Peripheral Orbital Atherectomy System (OAS).

The Hong Kong case is the first commercial use of Peripheral OAS outside of the USA. Bryan Yan, associate professor, Chinese University of Hong Kong, who treated the first patient in Hong Kong, says, “Patients with severely calcified peripheral arteries can be difficult to treat due to the limitations of traditional angioplasty or stenting.

This can also place patients at risk for subsequent complications including repeat interventions and amputation.

The commercialisation of the Stealth 360 OAS in Hong Kong provides physicians with a minimally invasive treatment option for this complex patient population. I am very satisfied with the procedural outcome for my patient because I was able to avoid implanting a stent in the distal superficial femoral artery and I look forward to continuing treatment of similar patients with this technology.”

Scott Ward, chairman, president and CEO of CSI, says, “We are pleased that the first patient treated with OAS in conjunction with our international distribution partner, OrbusNeich, was a success. This positive outcome demonstrates our mutual mission to support physicians in treating patients

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with peripheral artery disease.”

Scott Addonizio, senior vice president and chief operating officer of OrbusNeich, concludes, “Our experienced sales force is thrilled to bring CSI’s orbital atherectomy technology to Hong Kong. This first procedure occurred only two months after becoming CSI’s international distribution partner. We look forward to introducing CSI’s atherectomy technology to physicians in new markets in the months and years ahead.”

In July 2018, CSI announced that it had signed an exclusive international distribution agreement with OrbusNeich to sell its coronary and peripheral OAS outside of the USA and Japan.

Additionally, in January 2018, CSI announced that it was the exclusive US distributor for OrbusNeich balloon products. Ultimately, CSI will offer a full line of semi-compliant, noncompliant and specialty balloons for both coronary and peripheral vascular procedures. OrbusNeich PCI balloons include the Sapphire II Pro, the first and only 1mm coronary balloon available in the USA. In November 2016, CSI announced that Medikit, signed an exclusive distribution agreement to sell its coronary and peripheral OAS in Japan.

Cook Medical receives FDA approval for first 5mm

Zilver PTX (Cook Medical)

diameter SFA drug-eluting stent

Cook Medical have announced that a new 5mm diameter version of Zilver PTX was approved by the US Food and Drug Administration (FDA). It is the first 5mm drug-eluting stent in the USA with lengths available up to 140mm that is indicated to treat vessels as small as 4mm in diameter. The range of Zilver PTX stent diameters now available will address treatment of vessel sizes from 4–7mm in diameter.

The new diameter is better sized for smaller anatomy than previous sizes of the stent and provides an additional option to treat patients with lesions in their superficial femoral arteries (SFAs).

“We spend a lot of time listening to physicians to understand their clinical needs. Time and time again, they ask for more treatment options for peripheral artrial disease,” says Mark Breedlove, vice president of Cook Medical’s Vascular division. “We’re

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Product News excited to continue to develop the Zilver PTX line to answer those needs and help more patients around the world.”

The new size is the only 5mm drug-eluting stent on the US market for peripheral arterial disease (PAD) and provides another treatment option for lesions in patients with smaller superficial femoral arteries.

Zilver PTX was the USA’s first drug-eluting stent used in the treatment of PAD and is the only drug-eluting SFA stent with five-year published data. Zilver PTX has also been shown to cut re-interventions by nearly half through five years, compared to a combination of baremetal Zilver stents and percutaneous transluminal angioplasty (PTA).

Last year, Cook Medical introduced the 140mm-

length stent in both six and 7mm stent diameters and received expanded indications to treat lesions up to 300mm per patient. Zilver PTX also received an extended shelf life of two years by the FDA.

New Sniper balloon occlusion microcatheters cleared in Europe

Sniper

Embolx has been given the European CE mark for its latest Sniper balloon occlusion microcatheters. The devices are used to help deliver embolic agents in various procedures, including the treatment of tumours, uterine fibroids, and enlarged prostate.

The Sniper balloon occlusion microcatheters were recently cleared in the USA, gaining Food and Drug Administration (FDA) approval earlier this year.

The device occludes the vessel to alter blood flow-dynamics using pressure-directed embolization. It is currently used for the treatment of cancerous tumours in the liver and other organs, enlarged prostate (benign prostatic hyperplasia), and uterine fibroids.

“Our next generation devices incorporate experience from more than 1,000 Sniper balloon occlusion microcatheters used to date,” says Michael Allen, president and CEO of Embolx. “Now, interventional radiologists can do everything they would do with standard

microcatheters, but with the added benefits of balloon occlusion. This is a big step forward and provides physicians with the most advanced transarterial delivery system for tumour and prostate treatment.”

The Sniper comes in three lengths—110cm, 130cm, and 150cm— enabling access to femoral and radial arterial sites. Improvements in the microcatheter’s atraumatic tip allow for smooth entry and easy visualisation thanks to the radiopaque material, a press release informs. The Sniper is also compatible with conventional diagnostic catheters, guidewires, and embolic agents, so physicians do not require additional accessories.

This European clearance follows the news in April this year that the US National Institute of Health (NIH)’s National Cancer Institute awarded a US$2 million small business innovation research grant to Embolx to fund further research and development of the company’s Sniper balloon occlusion microcatheter.

Calendar of events 14–16 November

26–30 January

Bournemouth, UK

Hollywood, USA

BSIR 2018: British Society for Interventional Radiology Annual Meeting W www.bsir.org

8 December

Comprehensive Prostatic Artery Embolization (PAE) Course Barcelona, Spain

W www.EuroSTREAMpae.com

2019 22–25 January

ISET: International Symposium on Endovascular Therapy W www.iset.org

28–29 January

MIOLive 2019 (Mediterranean Interventional Oncology Live) Rome Italy

W www.miolive.eu

21–24 February

LINC—Leipzig Interventional Course

APSCVIR: Asian Pacific Society of Cardiovascular and Interventional Radiology

Leipzig, Germany

Bali, Indonesia

W www.linc2019.com

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Market watch

27 February–3 March

15–18 April

Vienna, Austria

London, UK

European Congress of Radiology (ECR) W www.myesr.org

23–28 March

SIR 2019: Society of Interventional Radiology Austin, USA

W www.sirmeeting.org

8–11 April

European Conference of Interventional Oncology (ECIO) 2019 Amsterdam, The Netherlands W www.ecio.org

Charing Cross Symposium (CX)

11–13 October

The Symposium on Clinical Interventional Oncology (CIO)

W www.cxsymposium.com

Hollywood, USA

9–12 May

com

Global Embolization Cancer Symposium Technologies (GEST) US

W www.interventionaloncology360.

New York, USA

W www.gestweb.org

22–25 July

The Society of Neurointerventional Surgery (SNIS) 16th Annual Meeting Miamia, USA

W www.snisonline.org

W www.apscvir2019.com

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