Interventional News Issue 75 ROW

September 2019 | Issue 75

Immunotherapy “destined to become an integral part of IO care”

“It is very important that we, as interventional oncologists, embrace the immuno-oncology field,” Thierry de Baère (Institut Gustave Roussy, Villejuif, France) said in his keynote address on the future of interventional oncology at the Society of Interventional Oncology annual meeting (SIO; 7–11 June, Boston, USA). Drawing from an SIO white paper published recently in Radiology detailing the challenges and opportunities of further integrating these two cancer disciplines and from the literature, de Baère outlines why “Immuno-oncology in cancer care is a fantastic opportunity for interventional oncology”.

Thierry de Baère during his keynote lecture at SIO

I

n the Radiology white paper, lead author Joseph Erinjeri (Memorial Sloan Kettering Cancer Center, New York, USA) and 17 other leading interventional oncology and immuno-oncology experts define the two IOs, and their potential importance in a more synergistic approach to cancer care: “Interventional oncology is a subspecialty field of interventional radiology that addresses the diagnosis and treatment of cancer and cancer-related problems by using targeted minimally invasive procedures performed with image guidance. Immunooncology is an innovative area of cancer research and practice that seeks to help the patient’s own immune system fight cancer. Both interventional oncology and immuno-oncology can potentially play a pivotal role in cancer management plans when used alongside medical, surgical, and radiation oncology in the care of cancer patients.”

Erinjeri et al, as well as de Baère in his keynote lecture, urge the interventional radiology community that this is possible with an increasingly close collaboration with medical oncology colleagues.

From an initial meeting on 23 January 2017 at the Memorial Sloan-Kettering Center in New York, USA, and through multiple subsequent teleconferences, the white paper authors evaluated key areas in immunooncology considered integral to the interventional oncologist’s practice.

“We are at the beginning of an exciting revolution in cancer care with the advent of immunotherapy,” Erinjeri et al summarise. “The role that interventional oncology

will play in immunotherapy will depend on our collective efforts to address rational questions regarding the fundamental immune effects of local and regional imageguided interventions.”

The SIO white paper makes four recommendations for future work on combining immunotherapy and interventional oncology. These are:

Standardise the lexicon between the two disciplines

Define commonly used immunobiology terms as they pertain to interventional oncology procedures and follow-up.

Establish criteria for identification of antitumour immunity, pro-oncogenic effects, and abscopal effects.

Harmonise the description of technique and procedural details (method of tissue injury, margins, particles, etc.) through standardised reporting.

Personalise interventional oncology

Determine the effect of organ, tumour type, and interventional oncology procedure on immune system effects through preclinical, translational, and clinical studies.

Investigate the timing of administration of immunotherapy in combination with interventional oncology therapies through clinical trials.

Create multi-institution registries to allow for largescale data mining and determination of correlations.

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A call to arms against “the tyranny of the randomised controlled trial”

“Arm yourself with the comprehensive but nuanced science behind hepatocellular carcinoma (HCC),” Riad Salem (Northwestern Memorial Hospital, Chicago, USA) instructed the audience at the Global Embolization Oncology Symposium Technologies (GEST; 9–12 May, New York, USA) during his Honorary Lecture, which concluded with the warning: “Do not let yourself be bullied by the tyranny of the randomised controlled trial”.

ARGUING THAT “SO-CALLED evidence-based medicine is really not [that] 90% of the time”, Salem challenged the notion that randomised controlled trials with a primary endpoint of overall survival should be the gold standard in interventional radiology. However, he began by conceding that “the randomised design is ideal—it is the best. It directly compares [the control] to the treatment, it minimises the bias and gives you causality where you can say ‘this treatment led to this endpoint’. You can power a randomised control trial with a large enough sample size that you minimise type 1 and type 2 error, and of course it is the most influential data”. However, though he says this is all possible in theory, he goes on to recount how in practice, this is often far from the case.

Speaking generally, Salem opined: “In interventional radiology (IR) and other areas, these are very expensive and complicated studies to do, with sample sizes that are sometimes impractical, if not impossible. They take years to complete and, as a result, what is their relevance [when completed]?”.

There is a precedent for using lower level data to inform procedural decisions

Salem argued that there are precedents for not relying on randomised controlled data to guide procedural choice. In the late 1990s, Salem informed GEST delegates that he used to perform a lot of Continued on page 2

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Latest news

September 2019 | Issue 75

Immunotherapy “destined to become an integral part of IO care” Continued from page 1

Understand the tumour-stimulating effects of interventional oncology procedures

Recognise patient/tumour characteristics and procedural factors that predict pro-oncogenic effects.

Identify optimal methods for eliminating unwanted protumorigenic effects.

Develop imaging biomarkers for interventional oncology procedures combined with immunotherapy

Require use of immune response criteria in addition to conventional imaging criteria in reporting response to interventional oncology treatments.

Validate new early imaging markers of therapeutic efficacy and response.

Design imaging studies that can assess the tumour microenvironment.

Combining interventional oncology therapies with intratumoral immunotherapy

Speaking to Interventional News, de Baère underlines the importance of the coordination of human intratumoral immunotherapy (HIT-IT) and interventional oncology. This year, the American Association for Cancer Research (AACR) held a specific session on HIT-IT at their annual meeting (29 March–3 April, Atlanta, USA), as do the European Society for Medical Oncology (ESMO; 27 September–1 October, Barcelona, Spain). The 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) will also host a full day of discussion and presentations on the topic (6–10 November, Fort Washington, USA).

This increasing international discourse on HIT-IT can be traced to an ESMO-sponsored expert meeting held 8 March 2018 in Paris, France. This comprised 11 experts from academia, 11 from the pharmaceutical industry, and two clinician representatives of ESMO. They met to produce a document that would “help to structure the ongoing and future development of HIT-IT”.

The resultant paper, published in Annals of Oncology by lead author Aurélien Marabelle (Villejuif, France) and colleagues, including de Baère, made six recommendations. These are: 1) To carefully select the paptient population for clinical trials, 2) To conduct translational studies systematically to facilitate better understanding of the mechanism of action of HIT-IT, 3) To organise face-to-face meetings

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between interventional radiologists, radiologists and/ or surgeons and oncologists, 4) To use ultrasound guidance for the injection of superficial tumour lesions, ultrasound guidance or CT-scans to guide the injection of deeper tumour lesions, and to use doppler ultrasound to ensure no big vessels are injected in error, 5) To measure injected and noninjected lesions at each injection time point to better capture the kinetics of tumour growth, and 6) To generate diagrams or photographs at every visit or time point of injection, which should be recorded on specific body-map proformas.

Erinjeri and colleagues state in their white paper that interventional radiologists need to work out how to monitor the effects of immunotherapy. They explain that “because immunotherapy mostly facilitates or modulates the inflammatory response rather than causing tumour cell death through cytotoxic effects, to our knowledge no specific guidelines exist to evaluate changes in tumour imaging appearance after treatment.”

Several response criteria have been developed, but to date none have been validated with intratumoural delivery methods or approaches combining locoregional therapy with systemically delivered immune-reactive agents. The SIO white paper authors claim this will be “essential” before physicians can successfully evaluate treatment response.

The group of 18 leading experts are categorical in their conclusion, stating emphatically: “Regardless of the challenges we face in investigating and incorporating immuno-oncology into an interventional oncology practice, immunotherapy is destined to become an integral part of interventional oncology care, and the integration is therefore essential for the future of IO.” In accordance with this sentiment, de Baère told the SIO audience: “Immuno-oncology will be a much bigger part of practice and research in the next five to 10 years. The reason for this is that we already know how great immuno-oncology is for cancer treatment.”

Showing a graph depicting the number of trials investigating intratumoural immunotherapy opening every year, he demonstrated their exponential growth; from fewer than five opening each year between 1992 and 2004, to 40 opening in 2017. de Baère argues that intratumoural delivery allows for a high enough local dose to efficaciously destroy the tumour, without the toxicity of systemic delivery. “We can help medical oncologists specifically target the tumours,” he said.

“There is a lot of noise about this,” he enthused.

Indeed, industry have started taking note, with some companies having their own dedicated compounds. One such example is Lytix Biopharma, which manufactures short, oncolytic peptides that cannot be delivered systemically. “Who can inject it locally?” de Baère asked the SIO delegates, “Interventional radiologists.

This is the future of interventional oncology, and it is very important that we are part of it”.

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A call to arms against “the tyranny of the randomised controlled trial” Continued from page 1

chemoembolization procedures. However, it was only in 2002 that Josep Llovet (University of Barcelona, Barcelona, Spain) and colleagues published in The Lancet findings from a randomised controlled trial that reported chemoembolization improved survival compared with conservative treatment. Writing at the time, Llovet et al said: “There is no standard treatment for unresectable HCC. Arterial embolization is widely used, but evidence of survival benefits is lacking.”

In response to this, Salem continued, “Before 2002, we were all performing chemoembolization based on phase II data”. However, Salem emphasised its limitations: “You have a 112 patient clinical trial with three arms; notice each arm is about 35 to 40 patients, so it is very small. This study here, that we all quote [to support the use of chemoembolization as the standard of care in unresectable HCC patients], basically was a single-centre study. There is a low sample size, there is no active control, so there is relatively limited power—all the things that we currently need in a randomised controlled trial are not necessarily present in this clinical trial.” In fact, the trial was stopped when the ninth sequential inspection showed that chemoembolization had survival benefits compared with conservative treatment.

Examining the evidence presented in the various guidelines that help inform physician’s practice, Salem reported a distinct lack of level 1 data. Of the National Comprehensive Cancer Network (NCCN) guidelines, Salem said: “95% of the recommendations are based on non-level 1 evidence”. Continuing through other frameworks, he stated that in the American Association for the Study of Liver Diseases (AASLD) guidelines, two of the 21 recommendations are based on level 1 data. He stressed that “everything else is lower level evidence”. The European Association for the Study of the Liver (EASL) guidelines tell a similar story: three of their 36 recommendations hinge on level 1 evidence.

Salem summarised: “We have guidelines that tell us what we should and should not do, yet most of them are not based on the very data that we are supposed to be generating, so there is some confusion. […]

As interventional radiologists, we have to recognise that many standards of care are not supported by randomised controlled trials, particularly with overall survival as the endpoint.”

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Randomised controlled trials

A call to arms against “the tyranny of the randomised controlled trial” Continued from page 2

He then goes on to enumerate the several procedures performed by interventional radiologists for which level 1 evidence does not exist: bland transarterial chemoembolization (TACE), drug-eluting bead (DEB) TACE, or Yttrium-90 (Y-90) TACE to treat HCCs or neuroendocrine tumours; ablation in colon cancers and HCCs; resection for colon cancer or HCC metastases.

“Liver transplantation,” he added, “a goal that many of us seek to achieve for our patients, a gold standard, curative option—what is that based on? A phase II, single-arm study published in 1996 and based on 48 patients. It is the standard of care, I understand that, but we have to make sure that we compare our therapies and their respective levels of evidence with what other standards are based on.”

Not all randomised controlled trials change clinical practice

“What we want are randomised controlled trials that provide clinically meaningful results. I think that is what we believe in interventional radiology,” Salem stated.

However, he went on to highlight how several randomised controlled trials were far from practice-changing.

Using the example of a phase III pancreatic cancer study published in the Journal of Clinical Oncology in 2007 by Malcolm Moore (Princess Margaret Hospital, Toronto, Canada) et al, Salem explained how, despite filling all the criteria for a randomised controlled trial, the results may still not be illuminating. Moore and colleagues set out to see if they could improve the chances of survival in patients with unresectable, locally advanced or metastatic liver cancer by adding erlotinib to gemcitabine. Comparing the erlotinib and gemcitabine group with the gemcitabine only cohort, the investigators found there was an overall survival

We have guidelines that tell us what we should and should not do, yet most of them are not based on the very data that we are supposed to be generating.” benefit of 9.9 days in the combined group. “More than 500 patients, level 1 evidence—and a survival benefit of 9.9 days,” Salem reiterated. “Is erlotinib and gemcitabine the gold standard? I am not a medical oncologist, I do not know, but this trial satisfies everything the purists really want when it comes to generating level 1 evidence. I do not know if it actually changes standard of care though.” A recent publication in Oncology Reviews by Amrallah Mohammad (Zagazig University, Zagazig, Egypt) concluded that “only [a] small set of patients get small benefit” from the combined use of erlotinib and gemcitabine.

Randomised controlled trials “do not necessarily reflect real-world outcomes”

Randomised controlled trials are often designed by statisticians and physicians to fit what is logistically possible, and therefore do not necessarily reflect realworld outcomes, Salem said. He uses several examples

September 2019 | Issue 75 to illustrate this point. Firstly, he explained how he suspects there is “a little bit of doctoring” going on when choosing the sample size for a randomised controlled trial: “Interestingly, if you look at many of these trials that we reported, sample size is 300, 400, 600—it is almost always an even number”. The sample size is the result of back and forth between the principal investigator and the statistician, and is, in theory, calculated from the initial hypothesis and the DELTA (difference elicitation in trials). Salem explains how, in practice, determining the sample size is often a case of calculating how many patients a physician believes they may realistically be able to enrol in a trial, and then “reverse engineering” a hypothesis and DELTA from that number (though he accedes he is “a little bit cynical”).

In addition to this alleged data engineering, Salem pointed to narrow inclusion criteria as slowing recruitment to trials. That so many are excluded slows recruitment, he said, and means that by the time enough patients are enrolled and have been followed-up, and the data have been analysed, the findings are no longer timely. According to Salem, there is “about a 90% non-enrolment rate”; he extrapolated from this that “the findings of a randomised study are [therefore] not applicable to 90% of the patients that you see, so it is a very strict patient population you are making conclusions about”.

Recruitment can also be an issue when enrolling for large, multicentre trials, Salem explained, due to the biases and beliefs individual institutions hold. In the mid-2000s, Salem and colleagues were designing a multicentre trial to compare Y-90 with RFA and TACE RFA. However, what was initially intended as a sixcentre clinical trial devolved into a single-centre trial of 45 patients. The investigators could not enrol enough patients in each of the three arms—Y-90, TACE and TACE RFA—because of physician and institutional preference over certain procedures. Nevertheless, Salem used the data derived from the beginnings of this trial to redefine the institutional standard of care at Northwestern Memorial Hospital to Y-90.

Using another example from his own work in liver cancer, Salem explained that the STOP-HCC trial, of which he is the global principal investigator, further demonstrates the difficulties of recruitment in a randomised controlled trial. The initial vision was to have STOP-HCC as an open-label, prospective, multicentre, randomised, phase III trial evaluating Yttrium-90 (Y-90) transarterial chemoembolization (TACE) in the treatment of patients with unresectable HCC. “In 2010, when we started the trial, all we had was sorafenib, and we wanted to see if this would add to the standard of care”, Salem said at GEST. “This started as a 400 patient clinical trial; it is now eight years later, the technique has improved, there are seven other drugs approved, and our sample size is now 600.

While I hope it will have an effect on standards of care, I am not sure what the impact of this trial will be, whether it is positive or negative.”

Overall survival “is not a good outcome for randomised trials with effective subsequent therapies”

Advising the listening interventional radiologists as to how he believes they should devise trials to further their field, Salem guards against using overall survival as a primary endpoint when the patient will receive multiple interventions. Quoting statisticians writing in the Journal of Clinical Oncology, Salem said that “survival is not a good outcome for randomised trials with effective subsequent therapies”. He elaborated: “We cannot attribute overall survival to the initial treatment, say TACE or radiofrequency ablation (RFA), if later on the patient had other interventions. After a patient progresses, they may be given regorafenib, lenvatinib, nivolumab, cabozantinib, ramucirumab.

This gets very complicated.”

Indeed, the Barcelona Clinic Liver Cancer (BCLC)

staging system (stages A/B) is predominantly predicated on level 2 data without data on overall survival. “It is too complicated to do overall survival studies, and there is a prohibitive statistical barrier”, Salem explained. “We must use imaging surrogates for BCLC A/B studies, such as time to progression and progression-free survival. Overall survival is possible in end-stage care, but really for everything else, we have to use imaging.”

He emphasised this point in his concluding remarks, reiterating: “I think in our quest to improve overall survival, we have let the statisticians rule a little too much, and we need to push back a little bit, and get a bit more clinical relevance in our clinical trials. For two therapies that might provide the same overall survival, we need to find surrogates that matter and reject the trope that overall survival is the supreme endpoint”.

Designing trials to push practice in interventional radiology

To combat these shortcomings, Salem made two proposals to the GEST audience for how interventional radiologists should go about designing trials in future.

Firstly, he suggested physicians conduct an initial, exploratory analysis. This would be an 80 patient study in a randomised, phase II trial design. “Forty versus 40, this bead versus that bead, this probe versus that probe”, Salem described. “Whatever it is you are investigating, you can compare it to a different option and make sure there is a difference you are identifying between the two.” If the investigators are aiming to change the standard of care, Salem suggested using this same model, but for 100 versus 100 patients: “If you cannot determine a difference in 100 patients versus 100 patients, there probably is not much there that is clinically relevant in the IR space”, he said. “Then you

We need to limit the weight we give randomised controlled trials.” do not have to get to a patient population of 1,000 and have a negative clinical trial.”

The second proposition Salem has for the GEST attendees is that investigators largely stop using overall survival as an endpoint, and use a clinically meaningful alternative. “I personally think response is a very important one”, he suggested. He explicated: “Imagine you have three treatments. One gives you stable disease, one gives you minor response, and one gives you major response. All three of those treatments have the same time to progression and the same progression free survival. But if you are a believer in the lethal tumour model in the liver, then the person with the best response rate is the person furthest away from the lethal tumour load line. So, everything else being the same, the best response becomes a relevant and important concept.”

He concluded: “I think we need to limit the amount of weight we give randomised controlled trials, and be careful not to prematurely and quickly discount other types of rigorously developed evidence. I think physicians rely on randomised controlled trials when supportive of their position, but interestingly ignore them when they do not; that is clear, we see that all the time.

“Do not accept in isolation the fact that we have limited level 1 randomised controlled trial data [in IR]. Take everything in totality—phase II, big data, randomised controlled trials—process, triangulate, and carry this knowledge to tumour board. You are certainly not alone in relying too heavily on phase II data, and please, whatever you are confronted with, do not let yourself be bullied by the tyranny of the randomised controlled trial.”

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Cancer guidelines

September 2019 | Issue 75

Society of Interventional Oncology requests updates to NCCN guidelines to more strongly recommend ablation The Society of Interventional Oncology (SIO) is working more closely within cooperative groups and taskforces, as well as amongst the guidelines commentariat, to provide a global voice to interventional radiologists working in cancer care. Within the various groups the society is active amongst, SIO president William (Bill) Rilling (USA) tells Interventional News they have the strongest presence on relevant National Cancer Center Network (NCCN) panels.

S

IO is working on developing and submitting evidence-based recommendations to various NCCN panels.

Commenting on this growing integration into the formal process of commenting on and reviewing guidelines, Rilling says: “We have been very welcomed into this process, especially by medical oncologists. Everyone can recognise that there is a benefit to the patient to have as broad a view as possible. The vast majority of people involved at the moment [with guideline review] are medical oncologists.”

NCCN kidney cancer guidelines

Earlier this year, updates to the NCCN renal guidelines were submitted by Ronald Arellano (Harvard University, Cambridge, USA), Thomas Atwell (Mayo Clinic, Rochester, USA), and S William Stavropoulos (University of Pennsylvania, Philadelphia, USA) on behalf of SIO. Their letter requests the NCCN kidney cancer guideline panel review six specific changes for inclusion in the management of T1a renal masses.

Speaking to Interventional News, Stavropoulos explains the society’s ambitions for how the guidelines will change: “We hope the NCCN guidelines are updated to accurately reflect the latest research showing the oncologic success and safety of percutaneous ablation for renal cell carcinoma (RCC) relative to surgery and active surveillance.

“It is critical that national guidelines reflect the latest developments in research and clinical practice. Updating the NCCN guidelines will help interventional oncologists at the local and national level.

Locally, it could help interventional oncologists during discussions regarding

requesting are: Move text related to thermal ablation to a position in front of surveillance.

When addressing relative incidence of local recurrence following thermal ablation compared to surgery, qualification is needed to state that both techniques are very effective and the difference in treatment success is very small or absent (5% or less). For small renal tumors, cancer specific survival is also similar amongst treatment strategies.

Benefits of thermal ablation deserve mention in Principles of Surgery.

When considering those patients appropriate for thermal ablation, please include “those patients willing to accept a potential very low increased incidence of local recurrence” and “those patients in whom partial nephrectomy is not possible and nephron preservation is imperative”.

Recommend the term “in selected patients” be removed below Ablative Techniques and Ablative Techniques be moved above Active Surveillance on page KID-1.

Recommend the following change be added to page Kid-B, 2-4, Follow-up

It is critical that national guidelines reflect the latest developments in research and clinical practice.

Updating the NCCN guidelines will help interventional oncologists at the local and national level.” treatment options at individual tumour boards. At the national level, updating the role of ablation in the NCCN guidelines could assist with issues such as funding of clinical trials, procedural reimbursement coverage and industry investment in research and development.”

These specific changes SIO are

after Partial or Radical Nephrectomy: Biopsy or repeat biopsy: New enhancement or enlarging nodularity along the surgical margin following partial nephrectomy or new enhancing mass in the surgical bed following radical nephrectomy.

Atwell outlines his ambitions for the

guidelines to Interventional News: “My hope is that we could bring the NCCN guidelines closer to those currently provided by the American Urological Association (AUA) and the American Society of Clinical Oncology (ASCO), both of whom include thermal ablation as a front-line treatment alternative for small renal masses. There are particular attributes of ablation that warrant consideration in the NCCN guidelines, including favourable perioperative outcomes.”

Enthusing about the society’s involvement in these requested guidelines changes, Stavropoulos says: “SIO has been critical in spearheading these type of efforts. For interventional oncology (IO) to take its place as the fourth pillar of cancer care, we need to engage with the major oncology organisations. In this instance, the SIO was instrumental in bringing our RCC working group together and helping us through the specifics of the NCCN submission process. Other areas of SIO advocacy include establishing the first IO Working group within ECOG-ACRIN [a cancer research group formed from a 2012 merger between the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network], spearheading multiple IO clinical trial concepts in gastrointestinal (GI), genitourinary (GU), and thoracic oncology within the National Cancer Institute (NCI) Cooperative Groups.

Establishing a footprint within organised oncology increases the visibility of IO and recognition of what we offer patients among our medical, surgical and radiation oncology colleagues.”

NCCN breast cancer guidelines

SIO also submitted updates to the NCCN breast cancer guidelines this year.

Submitted by Amy Deipolyi (Memorial Sloan Kettering Cancer Center, New York, USA), Maureen Kohi (University

of California, San Francisco, USA), and Gloria Hwang (Stanford University, Stanford, USA).

Deipolyi explains to Interventional News: “The NCCN publishes guidelines that guide physicians and patients on ‘standards of practice’ for cancer treatment. These guidelines not only drive decision making in tumour boards and in clinic, but are also used by insurance companies to justify witholding reimbursement for procedures and diagnostic exams. The current NCCN guidelines for breast cancer do not mention minimally invasive procedures, despite good evidence that local therapies are effective for palliating pain and liver-directed therapies can confer progression free survival intervals. The NCCN committee for breast cancer does not include a single diagnostic or interventional radiologist. We have petitioned the committee to consider including radiologists, and to consider minimally invasive therapies in the treatment of metastatic breast cancer. Our hope is to improve patient outcomes and to help physicians offer these procedures while minimising the difficulty in obtaining insurance coverage. We appreciate the support and effort of SIO to advocate for interventional oncology physicians and their patients.”

To this end, their letter suggests including a section for locoregional therapies for stage IV metastatic breast cancer and illustrates three clinical examples.

These three clinical examples are: if the patient has painful bone metastases, for oligometastatic disease, and for liverdominant hepatic metastasis refractory to systemic therapy.

Regarding the first example, the authors write: “Bone metastasis occurs in 65–75% of patients with metastatic breast cancer.

Image-guided cryotherapy, heat-based thermal ablation, and cementoplasty have been demonstrated to be effective and fast-acting methods to improve bone pain due to metastasis from a wide range of tumours, including breast cancer.”

Similarly, for oligometastatic disease, Deipolyi, Kohi and Hwang justify their recommendation through this statement: “Local ablative therapies for five or fewer sites of metastasis have been shown to provide longer progression free survival and may prolong overall survival.

Hepatic resection and/or thermal ablation of hepatic oligometastatic disease can confer disease free intervals lasting several years and perhaps, more importantly, allow long intervals of disease control without chemotherapy.

This is particularly beneficial in patients not tolerating systemic therapy.”

For their final clinical example, they expand: “Liver metastasis commonly occurs in breast cancer patients and is associated with poorer oncologic outcomes. Liver tumors may cause abdominal pain or result in compression of the portal vein or obstruction of bile ducts. In selected patients who are not eligible for resection Continued on page 9

Future clinical care

Issue 75 | September 2019

Society of Interventional Oncology requests updates to NCCN guidelines to more strongly recommend ablation Continued from page 6

or ablation, transarterial therapies such as chemoembolization and radioembolization have demonstrated radiologic responses that translate to prolonged patient survival. Combining liver-directed treatments in the management of metastatic breast cancer with liver-only or liver-dominant disease can provide longer disease control while delaying the need to change to another line of systemic therapy. Also, in patients with hormonally responsive breast cancer and new-onset liver metastases, transarterial locoregional therapy can delay the initiation of systemic chemotherapy and benefit the patient’s quality of life.”

NCCN lung cancer guidelines

Additionally, SIO submitted updates to the NCCN non-small cell lung cancer guidelines. The letter was penned by Patrick Eiken (Mayo Clinic, Rochester, USA), Florian Fintelmann (Harvard Medical School, Cambridge, USA) and Robert Suh (David Geffen School of Medicine at UCLA, Los Angeles, USA), and requests updating the role of imageguided thermal ablation in the Clinical Practice Guidelines in Oncology for non-small cell lung cancer.

The letter authors describe imageguided thermal ablation as “inclusive of radiofrequency ablation, microwave ablation and cryoablation” and as “a form of ‘local therapy’ or ‘local

ablative therapy’ and, generally, may be considered as a potential alternative to other local therapies, particularly for lung lesions <3cm”.

They argue for the inclusion of a section on the principles of imageguided thermal ablation in the NCCN

Updating the role of ablation in the NCCN guidelines could assist with issues such as funding clinical trials.” non-small cell lung cancer guidelines, as well as the addition of a section titled “Image-guided thermal ablation” in the discussion of treatment approaches in the guidelines. Currently, the guidelines include a similar section on the principles of radiation therapy; Eiken, Fintelmann and Suh say that as imageguided thermal ablation is “increasingly being studies and used clinically in the treatment of lung cancer”, including a summary of what it is and of its appropriate applications “would be useful to include”.

The third specific change called for by these interventionists is to give greater attention to ablation for medically inoperable stage IA cancer under the “initial treatment” options. Currently, when deemed medically inoperable, the guidelines suggest stereotactic ablative radiotherapy (SABR), with two footnotes, m and n. SIO is calling for NCCN to delete footnote “n” (which reads “Interventional radiology ablation is an option for selected patients”) and to include image-guided thermal ablation in the algorithm proper, alongside SABR. They state their rationale for this: “A growing volume of literature shows the efficacy of imageguided thermal ablation for local control of primary and secondary malignancies of the lung. While the evidence for surgery or SABR may be more robust, use of image-guided thermal ablation may expand the pool of patients for whom local tumour control is possible.

Image-guided thermal ablation may be of particular value in patients with limited pulmonary reserve or for those who have reached the limits of tissue toxicity from radiation therapy.”

A further five changes are specified in the letter: To swap the positions of “Radiation” and “Ablation”, so that ablation is a higher consideration for patients with multiple lung cancers where definitive local therapy is possible. To change “Ablation” to “Image-guided thermal ablation”. The authors justify this recommendation: “In the setting of multiple lung cancers, preservation of lung parenchyma and feasibility of repeat treatments are paramount considerations, as repeat treatments are expectedly necessary over time.

SIR publishes new training guidelines for endovascular thrombectomy The Society of Interventional Radiology (SIR) has published new training guidelines for endovascular stroke treatment. This is the first update since 2009, when the society released training guidelines for intra-arterial catheter-directed treatment of acute ischaemic stroke.

“O

bviously, the world of stroke intervention has changed tremendously since then”, lead author of the guidelines David Sacks (The Reading Hospital and Medical Center, West Reading, USA) tells Interventional News. At the time, catheter-directed thrombolysis was the only such therapy studied in randomised trials. In the intervening decade, mounting positive evidence for endovascular thrombectomy from randomised trials and metaanalyses, and the subsequent growth in the number of these procedures being performed each year, has led the SIR to believe that these new recommendations are timely and necessary.

The guidelines were authored by a diverse group of specialties: interventional radiology, interventional neuroradiology, endovascular neurosurgery, and stroke neurology, and included both academics and community hospital staff; they varied to being freshly out of training themselves, to having over 30 years’ experience of stroke interventions. Sacks explains to

this newspaper: “We solicited people from a range of backgrounds so that we could have a diversity of opinion, experience and knowledge. We wanted to make sure that we were meeting the needs of people in many different environments, as well as meeting the

[The new guidelines] make clearer what training and experience interventional radiologists are expected to have to be performing these procedures in North America.”

9

Both lung parenchymal sparing and repeatability are strengths of imageguided thermal ablation relative to radiation.”

Add “Image-guided thermal ablation” as a third option, after surgical resection or SABR, for patients where definitive therapy for local disease is feasible. The rationale for this is described thus: “A growing volume of literature shows the efficacy of imageguided thermal ablation for local control of primary and secondary malignancies of the lung. While the evidence for surgery or SABR may be more robust, use of image-guided thermal ablation may expand the pool of patients for whom local control of the tumour is possible. Image-guided thermal ablation may be of particular value in patients with limited pulmonary reserve or those who have reached the limits of tissue toxicity from radiation therapy.”

To add image-guided thermal ablation into the footnote that defines “Definitive local therapy for metastatic site”. This currently reads: “Typically, RT (including SABR) or surgical resection”.

To add “Image-guided thermal ablation” to the algorithm proper under “External-beam RT or SABR” and delete the footnote (where it currently resides) when recommending therapy for recurrence and metastasis.

On NSCL-19, 20, 22 and 23, change each instance of “Consider definitive local therapy (e.g., SABR or surgery) for limited lesions to “Consider definitive local therapy (e.g., Imageguided thermal ablation, SABR or surgery) for limited lesions.

needs of patients.”

However, no official representative of the Society of NeuroInterventional Surgery (SNIS) participated in the creation of these guidelines. Despite the SIR inviting various leaders and former leaders of SNIS to participate in the creation of these guidelines, “for various reasons those individuals declined”, as Sacks reports. Several of the guidelines authors are members of SNIS, though.

Sacks also adds, “We [SIR and the guidelines authors] have maintained lines of communication with the current leaders of SNIS, and we remain open to working with them in whatever ways would advance patient care for stroke interventions”.

“Interventional radiologists are seeking guidance as to how they should train”

Earlier this year, SIR, the Cardiovascular and Interventional Radiology Society of Europe (CIRSE), and the Interventional Radiology Society of Australasia published a joint position statement in the Journal of Vascular and Interventional Radiology (JVIR) outlining the role of interventional radiologists in acute ischaemic stroke interventions.

Sacks, who was also the lead author of this joint statement, describes this as “an acknowledgement that interventional radiologists have an important role to play in stroke care”, but adds that “it was also cautionary, stating that interventional radiologists must be adequately trained”. These latest guidelines provide the training pathway alluded to in the earlier joint statement.

Sacks says that the new guidelines “make Continued on page 11

Neuroendovascular interventions

Issue 75 | September 2019

11

SIR publishes new training guidelines for endovascular thrombectomy Continued from page 9

clearer what training and experience interventional radiologists are expected to have to be performing these [endovascular stroke] procedures in North America”. He continues: “There are an increasing number of interventional radiologists who are already involved in stroke interventions, and like any kind of medical care, there will be a range of experiences and capabilities. We are trying to bring more uniformity at a high level of what that training and experience should be. There are already many hospitals that are turning to their interventional radiologists to help provide this care, and those interventional radiologists are seeking guidance as to how they should train. They want to do a good job, and they need to know what the recommendations are for them to train to be able to do the good job they are committed to.”

Endovascular thrombectomy procedures on the rise

“I think the number of stroke interventions will continue to increase,” Sacks predicts. The current number of stroke interventions are vastly fewer than the number of patients generally acknowledged to be eligible. A 2018 survey from the European Stroke Organisation (ESO), the European Society of

Minimally Invasive Neurological Therapy (ESMINT), the European Academy of Neurology (EAN) and the Stroke Alliance for Europe (SAFE) investigated the access to and delivery rates of stroke care in 44 European countries—and found that over 65,000 stroke patients eligible for endovascular treatment were not provided with this intervention. On average, 1.9% (95% confidence interval [CI], 1.3–2.5) of all patients with an ischaemic stroke in Europe received endovascular treatment, while a recent UK study estimated that approximately 10% of stroke patients are good candidates.

The most common reason that stroke intervention was not performed on an eligible patient was the lack of adequately trained physicians, leading Sacks to argue that there is a need for well-trained interventional radiologists to perform these procedures. “Having more interventional radiologists

I think the number of stroke interventions will continue to increase.”

who are adequately trained will allow more patients in total to be treated when it is appropriate to treat them”, he says.

In addition to the potential increase in stroke interventions caused by treating a greater majority of eligible patients, Sacks also believes the overall number of eligible patients will rise. “The estimates on which these articles are relying [for estimates of eligible patients] are based on the well-accepted indications: patients within six hours, patients with ICA-M1/M2 occlusions, and patients whose strokes are sufficiently severe but do not have large core [infarcts]”, he says. “Based on recent trials, elected patients are now being treated up to 24 hours after stroke onset. There are multiple trials underway looking at whether patients with mild strokes or patients with large core [infarcts] will benefit.

“I think that in the future, we are going to be treating increasing numbers of patients with a broader set of indications. Stroke patients will be treated at an increasing number of centres [in the USA] rather than [just at] the current number of thrombectomy-capable stroke centres. I think there will be more uniformity in the way people are training, and more uniformity in the expectations for outcomes.”

Transradial access is safe and effective for neuroendovascular procedures In the largest cohort study to date, new research from Jefferson (Philadelphia University and Thomas Jefferson University, Philadelphia, USA) demonstrate that transradial surgery, done via the wrist, is safe and effective for a broad range of neuroendovascular procedures, and gives patients faster recovery with less procedural risk. Neurointerventionalists most commonly use a transfemoral approach, threading instruments through arteries in the groin.

Pascal Jabbour

“DESPITE IMPROVED SAFETY shown in large cardiology trials, transradial brain surgeries via the wrist are much less common”, says senior author of the study and neurosurgeon Pascal Jabbour (Jefferson, Philadelphia, USA). “Neurosurgeons tend to prefer the transfemoral approach on which many of us were trained. But our research demonstrates that all kinds of neurological procedures can be done effectively and even more safely via the wrist.”

Transradial access has been widely adopted by interventional radiologists across a range of procedures, with many advocating for its use due to its [positive] clinical outcomes and patient satisfaction measures.

Jabbour and his team, including first author Omaditya Khanna, retrospectively examined the medical records of 223 patients who underwent 233 consecutive neuroendovascular interventions via radial artery access at Jefferson. The procedures included diagnostic angiograms, mechanical thrombectomies, arteriovenous malformation (AVM)/arteriovenous

shorter recovery times with transradial access. It is easier to ensure a blood vessel in the wrist has clotted, and so patients can go home shortly after surgery, rather than laying horizontally for four to six hours after transfemoral surgery. The mean procedure time was also shorter for diagnostic angiograms performed via transradial versus transfemoral access (18.8±15.8 vs.

39.5±31.1 minutes; p=0.025).

One of the most compelling reasons to change practice, says Jabbour, is that it eliminates the risk of rare but potentially dangerous complications of post-surgical bleeds in the groin and retroperitoneal area, which can be difficult to detect.

“Lying flat after certain kinds of brain surgery should be avoided in cases with high intracranial pressure, and yet it is the best way to prevent groin and internal bleeds,” comments Jabbour.

“For these cases surgery via the wrist is by far the safest option.”

The overall incidence of perioperative and postprocedural complications was investigated, and was found to be low across all procedures performed via

fistulae (AVF) embolizations, coiling, stent-assisted-coiling, Woven EndoBridge (WEB) intracranial aneurysm device placement and flow-diversion treatments of cerebral aneurysms, and carotid stent placement.

A subset of 66 patients who had undergone both transfemoral and transradial surgeries were selected to

All kinds of neurological procedures can be done effectively and even more safely via the wrist.” complete a satisfaction survey to assess their preference. As published in Stroke, the majority of patients—94%—said they preferred surgery through the transradial route.

In addition, patients overall reported

transradial access. Periprocedurally, only two patients had symptomatic radial artery spasm, and there were no instances of iatrogenic complications (such as vessel dissection, stroke, and haemorrhage).

In 10 cases (4.3%), the intended procedure could not be completed via a transradial approach, and, thus, femoral artery access had to be pursued instead.

Ten patients complained of minor postprocedural complications, although none required therapeutic intervention.

Jabbour and colleagues conclude: “Radial artery catheterisation is a safe and durable alternative to perform a wide range of neuroendovascular procedures, with a low rate of complications. On the whole, patients prefer transradial, compared with transfemoral, access.”

Transradial pioneer

Jabbour was one of the first neurosurgeons to perform brain surgery via the wrist and has continued to teach others this technique.

In 2016, Diogo Haussen (Emory University School of Medicine and Grady Memorial Hospital Marcus Stroke and Neuroscience Center, Atlanta, USA) and colleagues set out to describe the feasibility and safety of transradial access in the interventional management of acute ischaemic stroke. Publishing their findings in the British Medical Journal (BMJ), they concluded that failure of transfemoral access in the endovascular treatment of acute ischaemic stroke is uncommon, “but leads to unacceptable delays in reperfusion and poor outcomes.

Standardisation of benchmarks for access switch could serve as a guide for neurointerventionalists.

Transradial access is a valid approach for the endovascular treatment of acute ischaemic stroke.”

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Global Interventional radiology

A skill development initiative is establishing interventional radiology across Africa and Asia

An organised skill development initiative that started in late 2015 offering interventional radiology (IR) training for eight emerging economies has precipitated the development of a global network of trained personnel who can support IR programmes in challenging locations. The initiative has motivated the formation of national IR societies in Nepal, Sri Lanka, Bangladesh and Nigeria, all of which—in addition to Myanmar—now have dedicated IR programmes in their largest hospitals.

THE CONCEPT AND its success are reported in the Journal of Vascular and Interventional Radiology (JVIR)

by Sanjiv Sharma and Kartik Ganga (both Department of Cardiovascular Radiology and Endovascular Interventions, All India Institute of Medical Sciences, Ansari Nagar, Delhi, India).

“Integrating IR into clinical practice remains a big challenge in emerging countries in Asia and Africa”, the authors write. “Although IR has changed clinical medicine worldwide, the benefits of these advances have not percolated to the mainstream practice of medicine in these locations. Emerging countries have much to benefit from IR”. With this concept in mind, Sharma and Ganga report how they organised for a group of interested radiologists to travel to their centre and take part in observerships and short-term training courses, typically lasting three months.

Mongolia, Nepal, Bhutan, Bangladesh, Myanmar, Sri Lanka, Ethiopia, and Nigeria were the eight countries that participated in the initiative. Since its inception, 51 specialists from these countries have received observerships in IR procedures. These specialists represent a spectrum of disciplines, including radiologists, technologists, and nurses, in order to best help establish a comprehensive IR team in their hospitals, the authors say.

Attendees were provided with logistic and financial support during their training period (up to US$500 per month toward stay and up to US$200 per month for reimbursement of observership), as well as samples of consumables for starting an IR practice and various educational materials. These included textbooks and management protocols published by the Society of Interventional Radiology (SIR) and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

A further 15 educational events have also been conducted to international audiences to date, some at the authors’ own institution and some within the participating countries’ borders. “Emphasis was placed on teaching and building standards for the ethical practice of IR”, according to the study authors. There is currently no exit-level examination following training, but Sharma and Ganga state that they intend to introduce one this year. To further objectify the results of the initiative, they are designing a survey to assess the impact of their training scheme on alumni who have returned to their native hospitals and started their own specialty practice.

Trainees establishing their own practice was one of the target outcomes of the initiative. Sharma and Ganga explain that trainees “were encouraged to start an IR practice [on return to their native countries] and were

September 2019 | Issue 75 supported in decision-making and procedure planning by regular communication via various channels, including telephone, WhatsApp, and e-mail on a regular basis”. CME programmes and workshops in their local institutions reinforced this training, and periodic invitations to conferences held at the All India Institute of Medical Sciences updated this learning.

Another key component of the training initiative was to use web-based platforms as “force multipliers”, allowing for wider participation. Virtual lectures and CME programmes were held for audiences across Asia and Africa, and were in fact transmitted live to up to 56 countries.

Radiology residents at medical colleges in India with poor IR utilisation were offered a short stint at an established IR department to raise awareness of the discipline and to encourage recruitment. This aimed to provide first-hand learning experience to acquire basic IR skills, as well as networking opportunities.

This global network building is key: Sharma and Ganga attribute the success of the programme to the participation of experienced interventional radiologists from India, the USA, China, Germany, and the UK. “These individuals act as global ambassadors for IR and play an enormous role in both inspiring and imparting knowledge to the budding specialists as well as act as role models for them”, they say.

Although IR has changed clinical medicine worldwide, the benefits of these advances have not percolated to the mainstream practice of medicine in these locations.”

Sharma and Ganga have also shared a collaboration with the International Atomic Energy Agency (IAEA) to prepare a document outlining the relevance of IR in clinical medicine and methods of establishing it in emerging countries. An expert group formed under the aegis of the IAEA in 2015 has published a report entitled “The Needs of IR in Emerging World Countries”.

Keeping in mind that IR is variously recognised as a subspecialty of diagnostic radiology or as a distinct clinical specialty, Sharma and Ganga impress upon their readers the importance of establishing IR as its own specialty in Asia and Africa. Their work with the IAEA

Until IR gets incorporated and integrated into regional healthcare systems and university teaching programmes, the nascent regional IR community needs the support of international IR organisations.” aims to lay stress on this issue.

Collaborating with national and international centres of excellence and setting up more training centres are among the next objectives, according to Sharma and Ganga. They call for large international IR societies to lend their experience and organisation to help support this cause, concluding: “Problems with availability of IR equipment should be addressed by encouraging and fostering indigenisation and locoregional development of such technologies. Until IR gets incorporated and integrated into regional healthcare systems and university teaching programmes, the nascent regional IR community needs the support of international IR organisations.

“Our specialty shares natural collegial bonds that should be harnessed to help grow rather than wait for external governmental agencies to leapfrog administrative and financial red tape and sluggishness”.

Replying to a letter penned in response to their original JVIR article, Sharma and Ganga acknowledge the need to harness “the potential of medical students for the growth of IR”. They write: “The optimal education for the potential of IR in clinical medicine needs to be introduced in the medical curriculum at an undergraduate level. This will help promote undergraduates’ interest in investigating a potential career opportunity in IR at a formative stage of their medical careers. This will also help to better understand and incorporate IR into management algorithms in clinical practice for undergraduate teaching. Overall, this is the best way for promoting IR among budding medicine professionals. It fits well with the approach of other IR societies and initiatives as well. In the emerging world countries where radiology in itself is an elective rotation [...], introducing an elective posting in IR is a tough challenge.”

A map depicting the countries where the skill development initiative is taking place

Interventional radiology in Nigeria

Issue 75 | September 2019

“We are simply on a mission”: Interventional radiology is key to moving medicine forward in Nigeria Hammed Ninalowo Comment & Analysis There are fewer than five practising interventional radiologists in Nigeria today, a country of 200 million people. Hammed Ninalowo aims to change that ratio, founding the organisation IRDOCNIGERIA, with the aim of training an additional 100 interventional radiologists in his home country over the next decade. Having trained in the USA, Ninalowo describes the experience of performing the first ever transjugular intrahepatic portosystemic shunt (TIPS) in sub-Saharan Africa, and looks forward to the launch of the first interventional radiology training programme in the country in September this year.

W

hen I told my colleagues in the USA that I was considering performing a transjugular intrahepatic portosystemic shunt (TIPS or DIPS: direct intrahepatic portosystemic shunt) on a Budd Chiari patient in Nigeria, most said I was crazy. But I remember thinking, “If I do not do this, who will?” After extensive planning by myself and my team, we were able to pull the procedure off with an amazing clinical outcome. A 20-year-old woman who had had 33 litres of ascites drained from her body over the last three years at monthly intervals and had lost all muscle mass now has no ascites, has regained muscle mass, and is returning to school.

My story of practising interventional radiology in Nigeria did not start there, however. Pulling off the first TIPS/DIPS in sub-Saharan Africa is just a small fraction of our journey.

I was born and raised in Lagos, Nigeria, and left in 1999 to pursue an education, though I always had a homeward focus. I finished by Bachelor’s degree in 2003 and graduated medical school in 2010. While in medical school, I continued to look back to Nigeria, and spent the summer of my first year at a teaching hospital in Lagos. My guiding principle all through medical school regarding specialty and career choice remained “What can I bring back to my people?” I was involved in the care of a patient in the intensive care unit in my third year of medical school; he had undergone two endoscopies due to

bleeding varices, yet continued to bleed.

An interventional radiologist was called in and, through just a tiny hole in the neck, placed a stent graft and coiled off varices, triggering an immediate change in the patient’s haemodynamics. That was it. My specialty was chosen and my interventional radiology journey started.

I trained in diagnostic radiology at the University of Maryland (College Park, USA). My mentors always asked me what my future plans were, and it always circled back to what I planned to do in Nigeria.

centre with level one trauma and multiple transplant programmes.

In early 2018, I was ready to make my push into Nigeria and heard of a group in Nigeria called the Nigerian Society of Interventional Radiology (NiSIR). I learned this group was attending the Pan Arab Interventional Radiology (PAIRS) meeting in Dubai, UAE. I immediately bought a ticket. I met many bright minds, mostly working in the public sector, who had left the country to obtain training and were back in Nigeria providing amazing care to patients. However, there were significant frustrations, as they had not been able to open all the possibilities offered by interventional radiology in the public sector. One of these gentlemen was professor Ahmed Ahidjo, now the chief medical officer of the University of Maiduguri (Maiduguri, Nigeria), who I still credit as the real pioneer of interventional radiology in Nigeria. I knew I had trained at one of the best IR programmes in the USA and had been lucky enough to work and gain experience in a high-volume complex practice. I was ready to make my push.

I initially started by collaborating with the public sector—however, it was immediately apparent that the resources there were significantly limited, and getting things done in the government hospitals was a difficult task. I immediately changed my goals to: 1) Look for a progressive organisation that believed interventional radiology was possible in Nigeria and work hard to show what is possible at a complex level immediately providing care to patients; 2) Continue to collaborate with the public sector to create sustainability in the country. With these objectives, I founded IRDOCNIGERIA, a company providing IR services in Nigeria, and started the IR division of RAD-AID International Nigeria.

Since our first case in September 2018, we have completed many complex procedures, including complex venous recanalisations, TIPS/DIPS, transarterial chemoembolizatons (TACE), varicocele embolizations, uterine fibroid embolizations (UFE), biliary stenting, and recanalisation for chronic total occlusions using SAFARI, to name a few. We now

We need to improve the longterm state of healthcare in these [African] countries by focusing on people and services who are committed to full-time or long-term sustainabilitydriven projects.”

I took multiple trips to Nigeria during training to survey the state of medicine and also visited some of the local pioneers who had made a move back home in fields like interventional cardiology and changed the narrative as to what was possible locally. I went on to finish subspecialty training in interventional radiology at the University of Pennsylvania (Philadelphia, USA). I have since worked in a large hospital system in Pennsylvania (Geisinger health system), a tertiary care

offer any procedure in interventional radiology except for radioembolization.

In September this year, we are hosting a symposium at the University College Ibadan (Ibadan, Nigeria) with several SIR [Society of Interventional Radiology] faculty members, and we will launch the first training programme in Nigeria.

Achieving this has not been easy. The time spent across two continents has been a challenge—though the greatest challenge remains the supply chain

13

Picture taken after completing the first BTK CTO recanalization with the SAFARI technique in Nigeria

for interventional radiology in subSaharan Africa and the infrastructure in public institutions. It is no secret that interventional radiology consumables are not cheap, but the cost is a minor factor, as most manufacturers (except currently Medtronic) do not do business in Nigeria or many other African countries. There is something interesting going on with a lot of African economies; many markets have emerged in the last few decades, and with this, modern medicine is on the rise. African patients spend an incredible amount of money on medical tourism to places like India and the West. In a very small way, I have stopped a few patients from making these trips. We can keep and treat these patients in Africa and keep the money in Africa for Africa. It will require some sacrifice from the industry, but most of the sacrifice will have to be made by Nigerian physicians in the diaspora who have acquired a significant amount of knowledge and thrive in most of their chosen fields. I say the days of “Tent medicine and medical missions” are dying, as these do not create sustainability.

We need to improve the long-term state of healthcare in these countries by focusing on people and services who are committed to full-time or long-term sustainabilitydriven projects.

For me, I have simply been on a mission and I have not looked back. I can say with authority that the future of medicine, on any continent without interventional radiology, is no future at all. My goal in the short term is to transition my practice full time to Nigeria, a goal well known to those around me. A colleague in Nigeria uses the phrase #TheNigerianPatientsAreWorthIt, and I agree. Our journey has just started, but watch this space, as I am committed not only to Nigeria, but to collaborating across Africa to bring the life-saving minimally invasive procedures of interventional radiology to the continent at large.

Hammed Ninalowo is an interventional radiologist in Lagos, Nigeria.

Global embolization

Issue 75 | September 2019

Fair-Embo project maps interventional radiology services across the world Speaking at the 2019 annual meeting of the Cardiovascular and Interventional Radiology Society of Europe (CIRSE; 7–10 September, Barcelona, Spain), Vincent Vidal (Marseille, France) describes the Fair-Embo technique, detailing how to obtain the inexpensive embolic agents, the technical efficacy of the procedure, and his ambitions for the project’s future.

A

n initial preclinical study in a porcine model tested the feasibility and safety of arterial embolization with absorbable and nonabsorbable suture fragments. The investigators reported a technical success, demonstrating the proof of concept of the feasibility and safety of the so-called “FAIREmbo” procedure. Demonstrating the in vivo feasibility of the procedure led Vidal and colleagues to propose what they termed the “FAIR-Embo technique”. Writing in Cardiovascular and Interventional Radiology (CVIR) earlier this year, they concluded: “Embolization by absorbable and non-absorbable suture is a feasible and effective treatment, which opens up the possibility of global use of this inexpensive and widely available embolization agent”.

At present, Vidal is working with the French Society of Radiology (FSR) to send out a survey to countries with emerging economies—“potential Fair-Embo recipients”, in his words—to map interventional radiology services around the world. The survey will be sent to more than 3,000 email addresses across Africa, South America, Asia, the Middle East and eastern Europe. The survey asks basic questions about access to interventional radiology services, such as: ■ Do you have access to interventional radiology in your hospital/ town/ state/ country?

■ If yes, which kind of procedures are regularly performed: angioplasty? Embolization? Drainage?

■ How many interventional radiologists are working in your hospital/ town/ state/ country?

■ Do you have a contact with a local or national interventional radiology organisation or scientific society?

■ Do you have any difficulty with obtaining implantable medical devices?

Although the survey results are yet to be received, Vidal speaks to Interventional News about his expectations.

He tells this paper that he anticipates the results “mapping the places where interventional radiology is possible”, as the answers will delineate where in the world trained physicians are working, the availability of imaging hardware such as X-ray machines, and where access to implantable medical devices is an issue. “The final goal”, he says, “is to target the places where FAIREmbo will be helpful, and also where the existence of an educational programme will be useful as a first point of action”.

With this in mind, the future steps of the Fair-Embo project that Vidal envisions centre around creating a global community of interventional radiologists.

Initially, he plans to create a foundation with the capacity to fund a FAIR-Embo clinical programme in developing nations. Outlining this idea to Interventional News, Vidal enumerates the features of this potential future foundation: “We will get help from a proctor if necessary to set it up. I foresee the foundation as one which can offer tips and tricks to interventional

If this material becomes clinically available [as an embolic agent], it will be a game changer for developing and even for industrial countries.”

Afshin Gangi I would like to link [a potential] FAIR-Embo foundation with all the interventional radiology organisations around the world.”

Vincent Vidal radiologists working in low resource settings, which will help provide any necessary materials, and which can help elaborate an existing clinical research programme.”

Further to the development of a FAIR-Embo foundation, Vidal would like to link this with “all the interventional radiology organisations around the world”. Ambitious in his aims for the project, Vidal says that he would like to collect data from the FAIR-

A Figure 1: Fair particles

B

15

Embo community (such as the number and outcomes of embolizations performed) “in order to give feedback to international healthcare organisations such as the International Atomic Energy Agency (IAEA) and the World Health Organisation (WHO)”.

By taking these steps, Vidal hopes to create “a virtuous cycle”. He imagines it working thus: FAIREmbo will help to develop embolization practices in low resource settings; data collected from these procedures will help to obtain funding from international organisations; this funding will help interventional radiology research in the form of the development of clinical programmes in emerging countries.

At CIRSE, Vidal presented a new study demonstrating how to obtain non-spherical particles with suture material. Using scissors, he advises interventional radiologists to cut sutures into small fragments between 700 and 1,100 microns long. So called “FAIR particles” (Figure 1) are then injected via a catheter to the target site, and their technical success is demonstrated through post-embolization imaging (Figure 2).

Afshin Gangi (Strasbourg, France), CIRSE vice-president, is enthusiastic about FAIR-Embo, commenting: “Even if this concept is not adapted for all cases, if this material becomes clinically available [as an embolic agent], it will be a game changer for developing and even for industrial countries.”

Detailing why he thinks this, Gangi says to Interventional News: “Traumatic, post-partum or post-surgical bleeding is a major cause of mortality.

Until the late 1970s, operative management was considered the only legitimate course for blunt and penetrating abdominal and extremity vascular injuries.

Interventional techniques first popularised in the early 1970s now offer a wide range of solutions, principally using transcatheter arterial embolization. Various embolic agents (for example, coils or gelfoam) and particles may be used to stop or control bleeding. All these agents used individually or in combination can save lives by stopping life-threatening bleeding.

“An embolization performed by a well-trained interventional radiologist is essential in all centres dealing with bleeding—trauma centres, maternity wards, surgical units where high blood loss is common, to name a few. In developing countries, training interventional radiologists to safely perform embolization is key. However, regardless of IR training or the presence of an angiosuite with high resolution C-arm fluoroscopy capabilities, availability of the embolic agent is an issue. The idea of having an efficient embolic agent which is available anywhere and is cost-effective is very attractive.

“The idea underpinning ‘the FAIR-Embo concept’, which demonstrates the feasibility and efficacy of using non-absorbable and absorbable sutures, is about making a cheap embolic agent available everywhere. In addition to this availability, the benefits of this material are that it is inexpensive, can be temporary or permanent, that it leads to mechanical obstruction, and that suture fragments are easy to work with.”

C

Figure 2: A: Left kidney before B: Selective embolization C: Control post embolization

16

Uterine fibroids

September 2019 | Issue 75

Interventional radiologists should be involved in fibroid patient consultations, study concludes In 2013, the Dutch national guidelines on heavy menstrual bleeding were updated to include, for the first time, a recommendation that uterine artery embolization (UAE) be part of counselling for patients with symptomatic fibroids. Despite this, no increase in the number of UAEs being performed in The Netherlands was observed between 2012 and 2014, according to a recent report published in Cardiovascular and Interventional Radiology (CVIR) Endovascular by Annefleur de Bruijn (Amsterdam University Medical Center, Amsterdam, The Netherlands) and colleagues.

THE STUDY AUTHORS aimed to evaluate the implementation of UAE in The Netherlands and investigate influential factors concerning gynaecologists’ preference, counselling differences and knowledge. “The UAE/hysterectomy ratio in 2014 was 6.9”, they report, a calculation the authors deem “unacceptably low for a procedure with solid scientific level 1 evidence”.

Indeed, de Bruijn et al write that some “‘urban embolization myths’ tend to persist”, with 40% of gynaecologists in hospitals that do not perform UAE doubting the effectiveness of the procedure. In hospitals that do perform UAE, nearly half of the gynaecologists overestimate the chance of a surgical intervention after the minimally invasive procedure.

This research is specific to The Netherlands, but the authors say that “Although there is no scientific evidence from other European countries, oral communications at scientific meetings seem

to support” their findings.

In 40% of women with heavy menstrual bleeding, fibroids are present. Although multiple randomised controlled trials have concluded that UAE is a valid, safe, and effective alternative to hysterectomy for patients with symptomatic uterine fibroids, when de Bruijn et al initiated their study, they believed the procedure was “offered infrequently” and that its implementation seemed “slow”.

The 2013 Dutch national guidelines recommend informing the patient of the following outcomes five years after the initial treatment (UAE versus hysterectomy): an improved quality of life comparable to that of patients who underwent hysterectomy; faster recovery and return to work after UAE compared to hysterectomy; in 75% of patients who underwent successful UAE, no hysterectomy was needed.

The study investigators asked all 82 Dutch UAE performing and non-UAE performing

hospitals to send their annual reports detailing the number of hysterectomies and UAEs performed. The calculated UAE/ hysterectomy ratios were 7%, 7% and 6.9% in 2012, 2013, and 2014, respectively.

Additionally, de Bruijn and colleagues sent out questionnaires to the hospitals’ gynaecologists.

The survey indicates that gynaecologists working at UAE performing hospitals counsel more patients for UAE (20 patients a year) compared to their colleagues at non-UAE performing hospitals (10 patients a year). Furthermore, where UAE was performed, 64% of the hospitals (18 out of 28) involved interventional radiologists in the counselling process. At the remaining 10 institutions that do not involve the interventional radiologists in patient counselling but which do perform UAE, 57% of the gynaecologists thought it should be standard practice to include them.

Over a third of gynaecologists at

UAE- hospitals (37%, or 16 of 43) think interventional radiologists should not be involved with patient counselling. At UAEhospitals, 26% (11 of 43) of gynaecologists think interventional radiologists should not be involved in the patient counselling process; 28% (12 of 43) think they should be involved only if that is the patient’s preference.

The authors advocate for the involvement of interventional radiologists in the counselling process. Over half (51% in UAE+ hospitals and 52% in UAEhospitals) the gynaecologists working across all the hospitals surveyed mentioned that the patient declines UAE when counselled. de Bruijn and colleagues blame the lack of interventional radiologists in the counselling process, pointing to the fact that gynaecologists from all hospitals tend to overestimate the risk of reintervention.

To illustrate this, they highlight how the gynaecologists indicated the statement “the secondary hysterectomy rate is 50%” to be true. de Bruijn et al respond: “Literature (and also the guidelines) state there is a secondary hysterectomy rate of 28% after five years of follow up and 31% secondary hysterectomies after 10 years.

Apparently this has not reached the surveyed gynaecologists”.

They suggest “Good counselling should be based on facts and should be free of personal preferences of the health care professional. In the case of UAE, counselling is mostly performed by the physician that does not execute the actual procedure. This could be a major influence [on patients turning down UAE]”.

Uterine fibroid embolization

Issue 75 | September 2019

Pilot study finds post-UFE antibiotic use does not affect infection rates Post-procedural antibiotic use does not significantly affect infectious complication rates following uterine fibroid embolization (UFE), a recent pilot study concludes.

Presenting these data at the Global Embolization Oncology Symposium Technologies (GEST; 9–12 May, New York, USA), Omar Chohan (Christiana Care Health System, Newark, USA) told attendees that, in the small study group under investigation, foregoing post-treatment antibiotics did not result in an increased rate of endometritis.

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owever, Chohan acknowledges that the cohort is under-powered to demonstrate non-inferiority of the study group, and thus believes that the present pilot study serves as a model for a larger scale study evaluating the necessity of post-UFE antibiotics.

Chohan and colleagues set out to evaluate the necessity of prophylactic post-procedural administration of antibiotics after UFE in the prevention of procedurerelated infections. According to Chohan, current guidelines from the Society of Interventional Radiology (SIR) report limited data regarding antibiotic use and state that prophylaxis is at the “discretion of the treating hospital”, though preprocedural antibiotic use is recommended. Cohan also informs GEST delegates that, as cited in multiple studies, the role of post-procedural prophylactic antibiotic treatment is controversial. “There has been no study confirming whether we need it or not”, Chohan claimed.

The study investigators therefore conducted polling of 92 academic interventional radiology practices in the USA to determine whether or not they used postprocedural antibiotics following UFE. Of 27 responses, ten did and seventeen did not. Of the ten centres that did use post-procedural antibiotics, one used Levaquin/ Flagyl, seven used Ciprofloxacin, and two used Doxycycline.

Following this survey, Chohan and colleagues conducted their pilot study. Two-hundred-and-ninetythree patients undergoing UFE at a single community centre between June 2014 and June 2018 were enrolled in a retrospective cohort study, and divided into a control group and a treatment group. In the control arm, 144 patients were given both preprocedural and postprocedural antibiotics (the latter being oral Ciprofloxacin and 500mg BID over seven days). Meanwhile, the 149 patients in the study group were only given preprocedural antibiotics. There were no significant differences regarding patient demographics or procedure details between the two groups.

In adherence with the SIR guidelines, Chohan and colleagues administered a single dose of pre-procedural antibiotics to all patients. The primary endpoint of the study was infection rate (endomyometritis) within 90 days of the procedure. Embolization was performed using either Embospheres (Merit Medical) or Embozene (Boston Scientific). Ninety-day follow-up data were collected.

The difference in infection rates between the two groups was not statistically significant (p=1): one patient (0.7%) in the post-procedure antibiotic group had sepsis nine days after UFE and was treated with hysterectomy; two patients (0.7%) in the study arm had malodorous discharge at 10 and 15 days, respectively, after the treatment, and were subsequently treated with antibiotics.

Contextualising these findings, Chohan said at GEST that most major and minor infectious complications present within the first month following UFE. Minor complications, he commented, which occur in 0.2–5.9% of patients, often do not necessitate hospitalisation, the intravenous administration of antibiotics, or surgical intervention. Major infectious complications include pelvic abscesses (experienced by 0.3% of

86% of women who had UAE were able to get pregnant after, says small, retrospective analysis In a retrospective, single centre study, the vast majority of patients who underwent uterine artery embolization (UAE) were able to have a successful pregnancy after the procedure. This led Muthusubramanian Rajasekaran (Department of Interventional Radiology, HCG Cancer Centre, Bangalore, India) to conclude that UAE has “satisfactory and acceptable outcomes” concerning fertility and pregnancy amongst patients of reproductive age, as he informed the audience at GEST 2019 (Global Embolization Oncology Symposium Technologies; 9–12 May, New York, USA).

AS A COMMONLY performed interventional radiology procedure, UAE is used to treat a variety of pathologies, including leiomyomas (fibroids), arteriovenous malformations (AVMs) and post-partum haemorrhages. “However,” Rajasekaran told the GEST audience, “the beneficial effects of UAE over the surgical treatment are still up for debate in patients of reproductive age, as the adverse effects of the procedure on fertility and pregnancy are not known.” As such, Rajasekaran and colleagues felt further investigation into the effects of UAE on pregnancy and

fertility was warranted.

They conducted a retrospective analysis of their hospital records between January 2012 and January 2018, where they found that 42 patients had undergone UAE for various uterine pathologies. Of these, nine were excluded for being over the age of 35, three were excluded as they did not wish to get pregnant in the future, and two were lost to follow-up. This left 28 patients, with an age range of 22 to 35 years, for the analysis. Fourteen per cent underwent UAE to treat AVMs, 43% had post-partum haemorrhage, and the

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patients), septicaemia, and emergency myomectomy or hysterectomy (reported in 1.2–2.6% patients).

Chohan argues that this research is timely and important, given the global conversation regarding the risks of over prescribing antibiotics. He commented: “I think the standard of not using those post-procedural antibiotics makes sense, because otherwise you are giving patients an antibiotic that might alter their gut bacteria or you may inadvertently be increasing antibiotic resistance”.

Chohan was asked by an audience member about the source of infection in the one patient that developed sepsis and was treated with antibiotics. He replied: “Anyone given antibiotics could potentially become prone to another type of infection, but normally these patients are younger and are not prone to this. I think the standard of not using those post-procedural antibiotics makes sense because you are basically just giving them an antibiotic that might alter their gut bacteria or put them in a position where they are resistant to other things.”

When asked if, in his own practice, he routinely administered antibiotics after UFE, Chohan said “No, not routinely. We definitely select our patients, [and consider] whether they are high risk or not, such as [if they have] diabetes or smoke. Certainly if they have had infections in the past we will consider that. We carefully select the patients that we offer post-procedure antibiotics to.”

remaining 43% had fibroids.

Twenty-four (86%) of these 28 patients had at least one successful pregnancy after UAE, and 21% of the patients (six of the 28) had two successful pregnancies following the procedure. The majority of these women—62%, or fifteen of the 28—had normal vaginal delivery, and 38% (nine of the 28) had a caesarean section.

The average time interval for the first pregnancy after UAE was 15 months; the shortest time to pregnancy was six months, and the longest gap between pregnancy and procedure was 30 months.

No procedure-related complications were observed in any of these patients.

Of the four (14%) patients who did not get pregnant following UAE, one (4%) did not get pregnant at all, and three (11%) had miscarriages. When asked about whether there were any unifying characteristics of these three patients by moderator Robert Mitchell Ermentrout (Department of Radiology, Emory University School of Medicine, Atlanta, USA) at GEST, Rajasekaran said that when they were evaluating the patients during followup, they found nothing that specifically explained why these women in particular were having difficulty with pregnancy.

“The more data we have, the more likely that this will become more standard practice”

An American audience member asked Rajasekaran what the referral rate and process was like in India, and if it is standard practice for gynaecologists to transfer patients across to the interventional radiology department.

“We are still finding it hard to convince gynaecologists to refer patients to us”, Rajasekaran said. “The practice in India is for these patients to first go to the gynaecologist, and then it is their role to refer back to us.”

The questioner said that this is similar to the case across most of the USA we well.

He elaborated: “There are many patients who hear about UAE from advertisements, and that is actually how we built up a lot of our practice. A lot of gynaecologists have started referring many patients to us, and normally it is because the patient already knows about the procedure and asks about it in their consultation, from what I understand. But there is still a recommendation to have them evaluated for myomectomy if they do desire future fertility, at least in the USA. But I think anecdotally, at least in our experience—so this is unpublished—fertility is certainly a possibility for patients who have had this procedure [UAE], and I think the more data we have, the more likely that this will become more standard practice across the world.” Rajasekaran agreed.

Vanguard embolization

Issue 75 | September 2019

Call for prospective RCTs on left gastric artery embolization at GEST 2019 Clifford Weiss (Johns Hopkins University School of Medicine, Baltimore, USA) called for a prospective randomised controlled trial to investigate potential weight loss after left gastric artery embolization (LGAE) in patients with obesity at the GEST Symposium (Global Embolization Oncology Symposium Technologies; 9–12 May, New York, USA) this year. While he concluded that non-randomised trials report a statistically significant and clinically important post-procedural weight loss after the procedure, he says that, given the “limited data” available to interventional radiologists, better quality data are needed to confirm the efficacy of LGAE as an enabler of weight loss.

WEISS FIRST DEFINED the patient population in which he believes LGAE may be most beneficial. For patients with a body mass index (BMI) over 40, who are classed as “severely obese”, he says gastric surgery is an appropriate choice, whether open or laparoscopic. For patients with a BMI between 25 and 30, “a lot of options are available”, such as dietary changes and exercise. A treatment gap exists, for patients with a BMI of 30–40.

Before detailing the current evidence in favour of LGAE as a solution interventional radiologists may provide for these patients with intermediately obesity wanting to lose weight, Weiss insists that no “mechanical solution” will be the ultimate obesity treatment. “Any of these solutions […] may only serve as part of the solution”, he tells the GEST audience.

“Nothing is going to replace surgery as

the gold standard in the population of patients who have severe obesity. More than anything, [LGAE] will be a tool for motivation, or to decrease hunger, or maybe as a standalone tool for limited weight loss”. He also emphasised the psychological, genetic, environmental, sociocultural and behavioural elements of obesity, and the consequent need for an interdisciplinary approach to treatment.

Theoretically, the goal of LGAE is to remove hormone-producing cells from the blood. “Although this has not been fully proven,” said Weiss, “we believe ghrelin, the hunger stimulating hormone, is critical to this process.” By embolizing the left gastric artery, interventional radiologists hope to alter the balance of hunger and satiation hormones. Preclinical studies in both swine and dog models have demonstrated that the procedure leads to a

Musculoskeletal embolization may be critical for pain management in sports injuries Yuji Okuno (Okuno Clinic, Tokyo, Japan) gave an update on the status of musculoskeletal embolization for pain management and sports related injuries at the GEST Symposium this year (Global Embolization Oncology Symposium Technologies; 9–12 May, New York, USA).

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e began by detailing the first report on musculoskeletal embolization, published in the Journal of Vascular and Interventional Radiology (JVIR) in 2013 by himself and colleagues, which demonstrated the feasibility and efficacy of transcatheter arterial embolization (TAE) using imipenem and cilastatin sodium for tendinopathy and enthesopathy refractory to nonsurgical management. Local tenderness score, used as a proxy for pain, reduced rapidly following the procedure, and pain disappeared at three months.

Okuno and his colleagues were encouraged by the results of this pilot study, seeing potential in the procedure’s use to alleviate pain. Current understanding is that chronic inflammation leads to an increase in abnormal neovessels, and that embolizing these vessels and reduce pain and consequently the dependence on alternative pain management strategies, such as taking opioids. However, more data are needed to solidify TAE’s position as a pain management treatment, and Okuno

decrease in ghrelin and either a decrease in weight gain or an increase in weight loss.

Following preclinical studies, there have been multiple retrospective studies looking at LGAE in humans, as well as a few prospective single arm trials. The most recent of these Weiss mentioned to the audience was conducted by Mohamed Zaitoun (Zagazig University, Zagazig, Egypt) et al and published in the Journal of Vascular Interventional Radiology (JVIR). Zaitoun and colleagues found that LGAE is well tolerated and leads to clinically significant decreases in weight and glycated haemoglobin in obese, prediabetic patients. They reported a 9.4kg or 8.9% mean weight loss at six months (p<0.0001) and no complications.

Adding to this evidence, Weiss mentions his own physician sponsored IDE (investigative device exemption) single-arm, prospective clinical trial on 20 patients with severe obesity. All participants had a BMI over 40, and were lighter than 400Ibs. They were embolized with 300–500µm Embospheres (Merit Medical). The primary endpoints were weight loss and 30-day adverse events.

Weiss reported no major adverse events in this study population, and a minor adverse event in 27% (eight of 20) of the patients.

At 12 months, there was a mean weight loss of 16.8kg, or 6% of initial body weight. The mean excess weight loss was 11% at one year (p<0.01).

Describing a graph showing hunger and weight loss over time, Weiss elaborated: “Interestingly, the hunger dropped very acutely and then started to rise again. The

said at GEST that comparative studies of TAE versus a placebo and TAE versus another treatment are needed.

Recently, there has been an upswell in interest around musculoskeletal embolization. Sandeep Bagla (chair of Interventional Radiology at the Vascular Institute at Virginia, Woodbridge, USA) presented the positive results on an early preclinical study of GAE in 20 patients with mild to moderate knee osteoarthritis in spring this year at the Society of Interventional Radiology’s annual meeting (SIR; 23–28 March, Austin, USA). A randomised controlled trial focusing on GAE in a larger cohort is underway. Meanwhile, Mark Little (Royal Berkshire Hospital, Reading, UK) is the principal investigator for the first clinical trial examining GAE in knee osteoarthritis patients in Europe, GENESIS. A placebo-controlled randomised controlled superiority trial embolization in the knee headed by Steve Landers (Barwon Medical Imaging, Barwon Health, Geelong, Australia) has also recently completed enrolment in Australia.

Musculoskeletal embolization for pain management in athletes

Specifically thinking about sports injuries, Okuno believes musculoskeletal embolization will have a much larger role to play in the future of pain management for athletes. He gives two case examples at GEST. The first case report is of a 26-year-old male patient with patellar tendinopathy. The patient is a professional goal keeper for a football team in the Japanese top league, and does not wish to undergo surgery due to the slow post-operative recovery. The patient’s chief complaint is knee pain, which is exacerbated by running, jumping, flexing and kneeling, Okuno informed the audience, “all movement crucial to his profession”.

The goalkeeper was resistant to conservative treatment, having had one corticosteroid injection and two hyaluronic acid injections prior to trying TAE. Post-procedural imaging revealed that the abnormal

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weight loss continued, but then lagged behind [the change in hunger]. The hunger started to reverse [appetite increases] at the 13-week time point and then slowly afterwards the weight loss started to decrease as well. So hunger and weight change go hand in hand. Could this be a motivating procedure [to add to] already existing weight loss protocols?” he asked.

Weiss’ residents conducted a metaanalysis to see if they could detect predictors of weight loss after LGAE. They did a systematic literature search to identify studies that reported postprocedure weight changes and, after excluding studies performed for the primary purpose of treating malignancy, ended up with seven publications to examine. From their analysis, they determined the most common adverse events were transient abdominal pain and superficial gastric ulceration. The pooled results of the seven studies revealed a mean body weight loss of 8.73% and a mean absolute weight loss of 10.08% (p<0.001 for both figures). Younger age, female sex, and higher baseline ghrelin levels appeared to be positive predictors of post-procedure weight loss.

However, Weiss reiterated that interventional radiologists still have “a lot to learn” about this procedure. “This needs randomised controlled data; this is not yet ready to be conducted in patients.

There are a lot of data we still need to collect, and we must collect it in a unified and thoughtful way so that we can actually move this forward. I believe in data, and I believe that our data so far is promising.”

I am very optimistic about this being a new area of embolization in the future.” vasculature was no longer visible, and the patient’s pain score as measured by the Numerical Rating Scale (NRS) dropped from eight to two within a month, and was zero three months post TAE. Two days after the procedure, the patient returned to light training, and was back to full training two weeks post-embolization. Six weeks’ postprocedure, the patient had their first competitive game.

“The patient had rapid progression and quick reduction in symptoms after the embolization”, Okuno described.

He opined, “This is particularly advantageous for sportspeople, as they cannot rest for long. At two-years follow-up, this patient’s knee has a normal appearance”.

The second case Okuno presented to the GEST audience was a chronic hamstring injury in a long distance athlete, who competed at the Rio Olympics.

The 34-year-old female complained of hip pain, and was resistant to conservative treatment after one year.

“It is very difficult to have surgery and then go back to training”, Okuno explained, “so she was reluctant to have that treatment, even though this was recommended surgery by the orthopaedic surgeon”. Instead, Okuno performed embolization twice in two months. She was back training again after three to four months.

Okuno used these success stories to promote the potential of embolization to allow athletes and active patients to continue engaging in their chosen sport pain free. Marc Sapoval, who was chairing the session “Vanguard in embolization” at GEST, said in response to Okuno’s presentation: “I am very optimistic about this being a new area of embolization for the future”.

Prostate artery embolization

Issue 75 | September 2019

Using smaller microspheres does not improve PAE outcomes Prostate artery embolization (PAE) outcomes do not differ significantly when microspheres of different sizes are used as embolic agents, a recent single centre, randomised controlled clinical trial reports. Writing in the Journal of Vascular and Interventional Radiology (JVIR), the authors report no differences between the clinical success rates using 100µm- to 300µm-sized particles at 18 months, although the incidence of minor self-limiting complications such as dysuria was greater with smaller particles.

“PARTICLE SIZES USED for PAE range between 50µm and 300µm for non-spherical polyvinyl alcohol (PVA) particles and between 100µm and 500µm for spherical embolic agents. The best size with which to obtain optimal clinical success is not known”, senior author Tiago Bilhim, lead author Daniel Torres (both Hospital Saint Louis, Lisbon, Portugal) and colleagues write.

Therefore, they set out to investigate the safety and efficacy of PAE using trisacryl gelatine microspheres of different sizes for the treatment of benign prostatic hyperplasia (BPH).

The study authors randomised 138

patients who underwent PAE for BPH between July 2015 and December 2016 to one of three groups: A, B and C. Embolization was performed using microspheres of different sizes in each group: in group A, the microspheres used were 100–300µm; for group B, 300–500µm microspheres; in group C, 100–300µm microspheres first, before being embolized with 300–500µm microspheres. All patients were evaluated before the procedure, and one, three, six, 12, and 18 months after PAE. At baseline, the International Prostate Symptom Score (IPSS), quality of life scores, and prostate volume were

“No clear benefit” in endovascular resection of the prostate, argues physician “There is no clear benefit in providing an ‘endovascular resection of the prostate’, as the traditional endoscopic route has proven to be very effective for the last decades”, argues Tiago Bilhim (Saint Louis Hospital, Lisbon, Portugal) in an invited commentary published in the Journal of Vascular and Interventional Radiology (JVIR).

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ilhim was writing in response to another article published in JVIR, by Lukas Hechelhammer (Kantonsspital St Gallen, St Gallen, Switzerland) et al, which was investigating the frequency and potential predictors of prostatic central gland tissue detachment (CGD). They describe CGD as “an enucleation-like reaction that sporadically occurred in a randomised controlled trial (RCT) assessing efficacy and safety of prostatic artery embolization” (PAE) versus transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). In their secondary analysis of 48 patients, Hechelhammer and colleagues found that CGD was present in three patients (6.3%), with one reporting spontaneous elimination of the necrotic prostatic tissue through the urethra. The two remaining patients had to undergo endoscopic procedures to remove the necrotic prostatic tissue due to urinary tract obstruction in one and urinary tract infection in the other.

comparable across all three groups (p>0.05). In group A, these were 23, 4.14, and 87.9cm3, respectively; for group B: 23, 4.09 and 89cm3; in group C: 24.2, 4.29 and 81cm3.

After PAE, the scores and data were: Group A: 9.98, 2.49 and 65.1cm3 (p=0.23) Group B: 8.24, 2.26 and 63.1cm3 (p=0.39) Group C: 10.1, 2.69 and 53.1cm3 (p=0.24) Specifically comparing groups A and B, the authors report no statistically significant differences in IPSS, quality of life or prostate volume. Detailing their results, Bilhim, Torres et al write: “The patients in whom the smaller particle size was used showed a significant regrowth in prostate size from three to 12 months, and there was an increase in minor adverse events in patients who underwent PAE with smaller microspheres, although this was not statistically significant.”

Indeed, the study investigators conclude that PAE using larger particles may be better, as there is a higher rate of minor adverse events when 100–300µm microspheres are used as embolic agents.

When a combination of microsphere sizes is used, as in group C, no benefit was seen compared to either groups A or B, and, compared with the 300–500µm cohort,

Hechelhammer and co-authors concluded: “CGD is a rare reaction that might be triggered by prostatic zonal anatomy, embolization technique, and mechanical or inflammatory processes. It should be considered in patients with severe postoperative pain and high CRP levels who experience voiding dysfunction after PAE to avoid complications. Investigation of larger cohorts might further elucidate this tissue response.”

Reacting to this research, Bilhim writes: “International Prostate Symptom Score (IPSS) and quality of life after PAE seemed to be similar between patients with CGD and those without CGD. When looking at the magnetic resonance images of patients with CGD and comparing them with patients without CGD, one is left with the impression that these patients almost have a ‘post-TURP’ appearance […]. These findings of CGD that was subsequently managed endoscopically mimic an assisted ‘endovascular resection of the prostate’.

The questions that immediately arise are: Is this a good thing? How much prostate do we want to destroy with PAE? What to do with the necrotic prostatic tissue that is left behind? How to avoid CGD?”.

All eight patients that have been reported with CGD in the literature were embolized with spherical embolic agents smaller than 300µm, says Bilhim (either 250µm Embozene microspheres from Boston Scientific, or 100–300µm Embospheres from Merit Medical). Other factors, including embolization technique, amount of embolic agent used, and baseline prostate volume, varied across these eight patients.

Bilhim therefore asks if the size of the embolic agent may be important.

Evaluating the evidence that helps elucidate whether or not the size of the embolic agent affects CGD, Bilhim first offers a “word of caution”. While some studies have found that adverse events are more frequent when smaller spherical embolic agents are used, Bilhim draws a distinction between the materials used, stating: “Polyvinyl alcohol (PVA) particles have also been extensively used for PAE with similar results so spherical embolic agents. Smaller sizes of PVA did not induce more adverse events after PAE and may lead to better functional outcomes, with conflicting evidence regarding symptomatic relief. It

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there was a higher rate of adverse events.

Bilhim, Torres and colleagues postulate that, as the number of minor adverse events was significantly lower in group B, the only study arm not to include 100– 300µm microspheres, the smaller sized particles were the culprit. They explain that the smaller sized microspheres “could penetrate more distally, causing more inflammation and necrosis”.

Drawing the reader’s attention to previous studies that have found an advantage to using smaller sized embolic agents (“The use of smaller PVA particle sizes led to greater prostate ischaemia, greater prostate volume reduction, and greater clinical improvement, without a higher rate of adverse events.

Retrospective analysis looking at spherical embolic agents has also shown that spherical embolic agents <300µm performed best”), the authors note that this potential benefit has to be counterbalanced by the potentially higher rate of adverse events and ejaculation disorders that they say has been “overlooked” in most PAE studies.

All adverse events were mild and self-limited, with the following rates (p<0.001): Group A: 86% (37 of 43) Group B: 41.3% (19 of 46) Group C: 58.3% (28 of 48)

is likely that the tendency for clumping and upsizing ‘protect’ the peri-urethral prostate from extensive necrosis with the smaller-sized PVA particles. There are no reports so far of CGD with PVA of any size or spherical embolics above 300µm in size.”

When comparing the patient experience of CGD after PAE with alternative treatments, Bilhim muses: “It seems that PAE is getting more and more similar to TURP”. Questioning if this is “a good thing”, he says “It is not clear”. He elaborates: “If one wanted to have a technique that is the same at TURP, then the need for such a technique would not be obvious, as TURP has been present for decades and remains the gold standard for symptomatic relief in selected patients with BPH. With more prostate destruction comes more adverse events; this is inevitable. We probably want to envision PAE as a minimally invasive technique that is better than medical therapy. It may not be as good at

How much prostate do we want to destroy with PAE? What to do with the necrotic tissue that is left behind?” relieving symptoms and urinary obstruction as TURP, but it clearly has a lower adverse event profile.”

Finally, Bilhim states that he believes “The future of PAE among all medical and surgical therapeutic options for symptomatic BPH will probably reside within the low adverse event profile. […] The potential for ejaculatory dysfunction after PAE with spherical embolic agents under 300µm and a higher adverse event profile with limited symptomatic gain questions its standard use, even if functional outcomes might be better.”

Bilhim’s own work, published in JVIR (see above) subsequent to this editorial, finds that PAE outcomes do not differ significantly when microspheres of different sizes are used as embolic agents.

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Ablation cost analysis

September 2019 | Issue 75

Ablation cheaper than Y-90 or TACE for the treatment of hepatocellular carcinoma Ablation costs are significantly less than those of transarterial chemoembolization (TACE) and Yttrium-90 (Y-90), according to a comparative cost analysis of the three procedures at a tertiary care centre. These results were presented at the 2019 annual meeting of the Society for Interventional Oncology (SIO; 7–11 June, Boston, USA) by Damir Ljuboja (Harvard Medical School, Boston, USA).

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juboja and colleagues used a relatively novel granular costing methodology developed by accounting academic Robert Kaplan (Harvard Business School, Boston, USA), called time-driven, activity-based costing, to estimate and compare the costs of TACE, Y-90 and ablation for the treatment of hepatocellular carcinoma (HCC) in their centre in Boston, USA. According to the investigators, “Only 36% of Medicare patients diagnosed with HCC receive cancerdirected therapy. Among them, TACE is utilised 10 times more frequently than ablation for these patients. Creation of an HCC-based bundled payment model may improve overall treatment utilisation, use of potentially curative treatments, and patient outcomes. However, the true costs of locoregional therapies are poorly understood.”

To gain a more accurate understanding of the costs of locoregional therapies for treating HCC, then, three observers prospectively recorded the utilisation time for staff members and equipment used to treat ten HCC patients with TACE, Y-90, and ablation procedures.

Previous cost comparative studies in interventional radiology have determined prices from Medicare reimbursement rates, whereas in this present study, the investigators prospectively calculated the costs themselves.

This bottom-up approach was intended to identify sources of variability in costs as well as provide a direct comparison between the expense of treatment modalities.

Ljuboja explained to the SIO audience the time-driven, activity-based costing methodology: “You first take a procedure and develop a process map for it, in which you identify each step from admission to discharge individually. Then, you prospectively measure [the duration of] each of those steps for each individual personnel member involved. For that person you can calculate a capacity cost rate using salary data, which allows you to estimate their clinical viability, usually measured in [US] dollars per minute. Multiply that by the number of minutes used, and you have the cost for that resource.” The costs of equipment and consumable supplies used in each procedure, as well as their number, were also recorded. The summation of all resource costs then gave the investigators the total procedure cost.

“We decided to do this prospectively initially. Small numbers of direct measurements are very time intensive and labour intensive, but it is very accurate”, Ljuboja

said of their approach. In addition to this prospective data collection, the investigators then retrospectively looked at the electronic medical record (EMR) to get time stamp data for the same procedures to verify if retrospective data can be used in place of prospective data. The difference between the retrospectively obtained data and the prospectively obtained data was not statistically significant for any of the three procedures, demonstrating that this analysis can be conducted retrospectively, saving time for the researchers. “Once we had validated that methodology”, Ljuboja continued, “we then retrospectively looked at all the cases from 2018”.

They found that total ablation costs, from admission to discharge, were US$3,813. This was 75% of the total cost for TACE (US$5,097) and 18% of the total cost of Y-90 (US$20,745). The cost for an ablation increased to

Consumables were the greatest cost contributor across all the procedures.”

US$4,245 for one versus two lesions treated, and increased again to US$4,461 for three lesions treated with two probes. The cost of TACE increased from US$5,097 to US$5,296 for non-selective (lobar) versus selective TACE. Breaking these results down, Ljuboja noted that the greatest personnel cost was observed in TACE. “A large function of that was use of the medicine attending and medicine resident, primarily because the patient was admitted overnight. Another notable thing”, he continues, “is the technologist cost for Y-90 procedures. This factors in to both the treatment stage and the planning stage.”

Fixed equipment costs were relatively low, “because the length of the procedures is short relative to the timeline on which these items are used”, Ljuboja explained. “For example, a CT scanner depreciates over the course of eight to 10 years, and if you atomise the cost of that CT scanner across that time horizon, then this is a relatively small amount of time we are talking about.”

Consumables were the greatest cost contributor across all three procedures and accounted for 63% of ablation,

57% of TACE, and 91% of Y-90 costs. “Of note”, Ljuboja wrote in his presentation abstract, “each procedure has a single consumable that accounted for a substantial portion of the overall procedure cost, namely ethiodized oil for TACE (30%), Y-90 resin microspheres for Y-90 (81%), and the probe for ablation (41%).”

“The point of these studies is to identify cost levers that we can pull to minimise the cost to overall maximise the way we are spending our money when it comes to following these procedures, so I think from our study we have identified that there are two different approaches that can be taken. One involves the use of alternative labour sources when it is clinically appropriate; the other is using collective bundled agreements with manufacturers to drive down the price of consumables and equipment”, Ljuboja concluded.

Acknowledging that one of limitations of this study is that it was conducted entirely at a single centre, Ljuboja told the SIO attendees that replication of these methods at other institutions will enable the investigators to determine the inter-centre variability in costs of these procedures, and additionally may allow for the creation of a representative national or regional bundled payment model to improve utilisation of locoregional therapies for patients with HCC. “As a specialty, we are a little bit guilty of navelgazing—we are looking inwards a bit. What might be really interesting is to extend some of your methodology to other cancer treatments. I mean radiation therapy, some chemotherapies, and immune oncology, because I think it might be quite surprising to the world to see what our true costs are versus some of the things that are done in other specialties”, commented Fred Lee (University of Wisconsin School of Medicine and Public Health, Madison, USA).

“One thing I will say to address that is that this methodology has been used in other specialties in the past,” a commenter responded from the floor, “primarily surgical specialties on the scale of singular events. A good example is total knee replacements, so they isolated that entire care cycle and calculated all the costs. It has been used to some extent in oncologic procedures, primarily in radiation oncology and surgical oncology, but I think in IR it is a relatively new concept, and we are one of the first studies to evaluate [our procedures in this way].”

Ljuboja noted that studies looking into costs often use Medicare reimbursement rates as the base data, and this does not allow the investigator to determine how best to bring costs down. The granularity of the data provided by the methodology in the current study—using the Harvardderived time-driven, activity-based costing method— enables exactly that. “As the payment landscape in the USA is moving toward alternative payment models— there is already an oncology care model—one of the biggest challenges that comes with that is that if you are asking payers to pay a bundled payment over the lifetime of a patient, you have to understand your true costs in order to actually generate a profit or make sure that your financial enterprise is viable. So this is where that work fits in,” he opined.

Automatic characterisation of Lipiodol deposition after cTACE may make predictions about tumour response Automatic characterisation of Lipiodol (Guerbet) deposition is feasible, workflow efficient, and improves consistency across patients, argued Sophie Stark (Yale School of Medicine, New Haven, USA) at the Society of Interventional Oncology’s annual meeting (SIO; 7–11 June, Boston, USA). Stark presented an automated quantitative and pattern-based method for the characterisation of Lipiodol deposits on CT scans taken 24 hours after cTACE (conventional transarterial chemoembolization).

“THIS WORK PAVES the way for the development of automated algorithms that predict tumour response from preprocedural MRI and 24 hour CT, and may allow earlier and more personalised therapy”, she enthused at the meeting.

“Lipiodol use in cTACE plays a unique multifunctional role”, Stark explained. “It

has drug delivery capabilities with transient microembolic effects, and its radiopacity allows drug delivery visualisation on post-procedural CT scans. Previous studies already show that Lipiodol deposition is correlated with tumour response.”

The investigators within the Yale Interventional Oncology Research Lab,

led by Julius Chapiro, set out to see if they could further establish Lipiodol as an early imaging biomarker for the therapeutic efficiency of cTACE using this automated system on 24 hour CT scans. Contextualising this research, Stark informed the SIO audience that liver cancer is the fourth leading cause of

cancer-related deaths worldwide, and that cTACE is a guideline approved treatment option for patients with intermediate to advanced stage disease.

Stark and colleagues utilised both these features of Lipiodol in their automated algorithms.

Continued on page 23

Transarterial chemoembolization

Issue 75 | September 2019

Figure 1: CT scan of liver with colour coded Lipiodol density overlay Continued from page 22

They conducted a retrospective study of 42 primary and secondary liver cancer patients, with a total of 65 tumours between them, who underwent cTACE between 2012 and 2018 at the Yale School of Medicine.

All patients had a baseline contrast-enhanced MRI scan before undergoing cTACE, then a CT scan 24 hours after the procedure, followed by a second MRI scan 30 days post-procedure. Detailing this image analysis workflow, Stark explained how she and her colleagues volumetrically segmented all of the tumours at all imaging time points. This was followed by an automatic, enhancement-based quantification of viable and necrotic tumour tissue on MRI. Next, the investigators performed an enhancedbased volumetric response assessment using qEASL (Quantitative European Association for the Study of the Liver).

“On the 24 hour CT, which was our focus, we characterised Lipiodol deposition automatically”, Stark continued. The researchers looked at the tumour coverage with Lipiodol, as well as areas of different Lipiodol densities— categorised as low, medium and high— using intensity thresholds from the Hounsfield units scale. The cut-off values were: low density, 87–145 Hounsfield units (HU); mid density, 155–240 HU; high density, 241+ HU. The automated quantification method was developed by one of Stark’s co-workers, Clinton Wang, who is currently a graduate student at the MIT in Boston, USA, and was previously involved with research at Yale. Based on these density values, the developed algorithm creates a colour coded overlay for the CT image of the liver, where low density areas were shaded green, mid density areas shaded yellow, and high density areas shaded red (see Figure 1).

Stark continued: “Specifically, we looked at homogenous deposition of Lipiodol, sparsity, rim deposition of Lipiodol, and peripheral deposition. The homogenous and sparsity deposition of Lipiodol could be determined through volumetric analyses of the whole tumour, whereas for the rim and peripheral Lipiodol deposition, a more complex approach was required.”

Expanding on these complexities, she said: “First, we calculated the volume of the tumour, and then created a sphere with exactly the same volume. Then we used operations such as morphological erosion and dilation to separate the core and the periphery of the tumour.”

Lipiodol coverage in viable areas was significantly higher than that of necrotic

areas, the investigators found through comparing contrast-enhanced MRI scans.

There was approximately 8.2% more Lipiodol coverage in viable areas than necrotic zones, averaged throughout all tumours. “We also looked at several subgroups, and the analysis was consistent throughout”, Stark said.

Looking at Lipiodol density distribution, the fraction of low density deposition was significantly higher in necrotic areas compared with viable areas, whereas the fraction of high density Lipiodol was significantly higher in viable compared to necrotic areas. There was no significant difference for mid density Lipiodol. Also, this analysis was consistent throughout several subgroups, according to Stark.

The investigators reported a stratification of tumour response by Lipiodol density. Areas that deposited Lipiodol became necrotic at a higher rate, as seen on follow up MRI, than areas without Lipiodol (p=0.0475). Higher concentrations of Lipiodol enhanced this effect—with increasing Lipiodol densities, there was an increasing percentage of necrotic tissue.

When deposited peripherally, Lipiodol is associated with an improved tumour Homogenous, non-sparse, and rim deposition were all associated with accelerating the slowing of tumour volume growth. In Stark’s words: “Homogenous deposition, non-sparse deposition, and rim deposition within sparse tumours showed an increased decrease of enhancing tumour volume on follow up MRI”.

This led Stark and colleagues to conclude that the automated characterisation of Lipiodol “can be easily incorporated into a standardised framework for cTACE management”.

Stark summarised: “Our approach improves the consistency for patients because it leverages the standardised Hounsfield units scale. We show that tumour enhancement on contrast-enhanced MRI can make predictions not only about the presence, but also about the density, of Lipiodol deposition, which is strongly correlated to tumour response to cTACE. Also patterns, including homogenous, non-sparse, rim and peripheral deposition of Lipiodol were positive predictors of tumour response. We think this work paves the way for the development of fully automated algorithms that can predict tumour response from pre-procedural MRI and 24 hour post-procedural CT, and may allow earlier and more personalised therapy to our liver cancer patients”.

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Interventional oncology

September 2019 | Issue 75

What is an interventional oncologist?

William Rilling Comment & Analysis Society of Interventional Oncology (SIO) president William (Bill) Rilling notes that you do not need to be a full time cancer specialist to describe yourself as an interventional oncologist, and that such a prescriptive definition is unhelpful. “Being an interventional oncologist is not about how many cases you do or what percent of your practice is IO, it is a mindset and a dedication to be a part of the cancer care team”, he says.

AS INTERVENTIONAL RADIOLOGY (IR) continues to evolve and mature, it seems only natural that the development of subspecialties is a part of that evolution. Currently, IR physicians may focus on a variety of subspecialty practices including peripheral arterial disease (PAD), venous disease, musculoskeletal interventions, women’s health, oncology, and many other new and exciting facets of IR. Encouraging and enabling IR physicians to focus on subspecialties is important to drive innovation and research and subsequently advance practice. From a practical perspective, the diversity and richness of IR practice helps protect us as IR physicians from large losses in patient and procedure volumes as we can often

compensate by expanding other areas of our practice. If a drug is developed tomorrow that cures atherosclerosis, many interventional radiologists would lose a significant and important part of their practice, but the vast majority would still have a job.

However, the diversity of IR can also be a weakness. Others who practice in the field of oncology, for example, focus exclusively on caring for cancer patients.

Very few medical, surgical, and radiation oncologists spend a significant portion of their time on anything but oncology. This presents a challenge for interventional oncologists, as there are very few IR/ interventional oncology (IO) physicians who practice in IO exclusively. It makes it more difficult for us to be part of

“the club.” For example, my practice is about 70% IO, but I also treat vascular malformations, hereditary haemorrhagic telangiectasia (HHT) patients, along with all the other things most of us take care of on a daily basis, and still have to be able to treat aortic catastrophes on call. Having a single-minded focus on oncology is a challenge for most interventional radiologists.

How do we overcome this challenge?

In my view, there are several solutions.

First and foremost, we must practice multidisciplinary patient care at its highest level with patients as the focus. Cancer care is the ultimate team sport and most cancer patients will have many different oncologic specialists caring for them at various times throughout their cancer journey. This requires the IR/IO physician to participate in multidisciplinary tumour boards, have a meaningful role in treatment decision making, see patients in clinic to discuss options, follow them in clinic to assess response, and understand the evidence basis for IO therapies and the complimentary medical and surgical options. If you are doing these things in your practice, even if IO is not the majority, you are an interventional oncologist. Thus, being an interventional oncologist is not about how many cases you do or what percentage of your practice is IO, it is a mindset and a dedication to be a part of the cancer care team, providing a unique perspective on image guided therapy and hopefully helping to move the field forward.

IR/IO physicians have a significant advantage being part of the cancer team: we have a role in cancer care from diagnosis, through treatment, and continuing to palliation. Therefore, the definition of what are “IO procedures” also warrants additional discussion.

Targeted biopsies are becoming increasingly important as personalised

Nanotechnology answers outstanding clinical questions in interventional oncology “Interventional radiology is uniquely equipped to shape the next generation of nanotherapeutics,” Sarah White, associate professor of Radiation and Surgical Oncology at the Medical College of Wisconsin (Milwaukee, USA) and adjunct professor of Radiology at Northwestern University (Evanston, USA) informed delegates at the 2019 annual meeting of the Society of Interventional Oncology (SIO; 7–11 June, Boston, USA). She presented research detailing how the local delivery of nanoparticles directly to the tumour site enables enhanced care to cancer patients.

“I

think nanotechnology really allows us to troubleshoot some of the problems in interventional oncology, and then to find applications and create solutions”, she said.

Globally, US$10 billion is spent on nanotechnology research, across many different disciplines. Explaining why she believes this technology has so much potential in the medical field specifically, White said, “Nanoparticles are the right size. One nanoparticle is a billionth of a metre. To visualise that: a marble to the size of the Earth. The diameter of a DNA double helix is 2nm, and the smallest bacteria is 200nm long. Nanotechnology is the size between cells and their organelles, such as mitochondria. They are right in

that cellular realm, which is why it is so advantageous to use them in this field.”

In cancer research, nanoparticles are usually used in a theranostic setting, meaning that the nanoparticle can be used not only as a drug—as the treatment— but also as an imaging tool. Currently, systemic chemotherapy used to treat cancer patients is non-specific and, due to lymphatic drainage of the chemotherapy agent from the target tissue, needs to be administered in such high doses to be concentrated enough in the tumour to destroy the cancer that side effects are common and severe.

However, when the chemotherapy drugs are formulated into a nanoparticle, these do not leach out of the tumour cells

cancer therapy expands at an exponential rate. We not only biopsy for initial diagnosis but also to identify new mutations and resistant clones to modify targeted therapy. This is a central and critical role in the cancer patient which will continue to expand. Image guided therapeutic procedures are clearly the realm of IO and we all need to work to expand access to these procedures for our patients. Central to this will be proving the effectiveness of IO treatments by expanding clinical trials and other data collection platforms. IO/IR physicians also play a unique role in palliation and improving quality of life for cancer patients with fluid management techniques, pain palliation, management of malignant bowel obstruction and many other interventions to improve quality of life and decrease narcotic usage in this patient population. This broad spectrum of involvement from diagnosis, to treatment and continuing to palliation is a unique advantage and perspective for IO. Moving forward, I believe we should continue to encourage and enable subspecialty evolution in IR. This does not weaken IR as a whole but strengthens it. As interventional oncology matures as a subspecialty, we should embrace our inherent and significant advantages as cancer specialists. Currently, as patient reported outcomes, quality of life metrics, and cost effectiveness all become central to cancer therapy, we have a unique opportunity to expand the role of IO and expand patient access to IO therapies. We will need all IO/IR physicians functioning at a high level in their cancer centres to accomplish these goals. The door is open, we simply must walk through it.

William (Bill) Rilling is professor of Radiology and Surgery at the Medical College of Wisconsin, Milwaukee, USA. the normal lymphatic outflow cannot form to drain the tissue correctly, altering what passes into and out of the cancerous cells. Smaller molecules, such as nanoparticles, can enter the tumour, and due to the lack of lymphatic drainage, remain there. This method of drug delivery is known as passive tumour targeting, and it increases the ability of the interventionist to get the drug into the tumorous tissue. Due to the proper lymphatic drainage of the non-tumour

I think nanotechnology really allows us to troubleshoot some of the problems in interventional oncology, and then [...] create solutions.” as easily. This is because healthy cells are packed close together in an orderly structure, and have tight junctions with a lymphatic outflow system threaded throughout. In comparison, tumour cells have antigenic factors that mean they grow rapidly, proliferating in a disordered fashion without tight junctions. The larger gaps between tumour cells means

cells in the body, the nanoparticles are filtered out of these more effectively, meaning the concentration of these small molecules is greater in the cancer.

Active targeting of the tumour

Active targeting of the tumour by Continued on page 25

Nanotechnology

Issue 75 | September 2019 Continued from page 24

nanoparticles also improves clinical outcomes. White explained at SIO: “Tumours often overexpress receptors, so we can put things on the nanoparticles to actively target those surplus receptors.”

According to White, this active tumour targeting increases the efficacy of the treatment due to greater internalisation of the chemotherapy agent.

Another drug delivery method explained by White at SIO is endothelial cell targeting, where, similarly to the overexpression of surface receptors on the tumour cells, investigators can formulate nanoparticles to specifically target overexpressed receptors on angiogenic endothelial cells. These line the newer blood vessels feeding the tumour, and using nanoparticles to target these cells helps eradicate the source of the blood flow to cancerous or benign growths.

“The last thing we can do [with drug delivery] is triggered drug release”, White described, “and this is one of the most interesting to me. We can stimulate the release of the cargo. The cargo is the imaging agent or the treatment.”

Clinical applications of nanotechnology in interventional oncology

Addressing the SIO audience, White described current and potential clinical applications of nanoparticles. The first example she used was in the delivery of hydrophobic drugs: “We want to deliver hydrophobic drugs. We think sorafenib can help us treat the surge in vascular endothelial growth factor receptor (VEGF) after transarterial chemoembolization (TACE) that we see at 24 hours.”

Sorafenib is currently the only first-line multi-kinase inhibitor approved for use in hepatocellular carcinoma (HCC). It inhibits the activity of several kinases, including VEGF, which are involved in tumour cell signalling, proliferation, angiogenesis and apoptosis. Thus, sorafenib inhibits tumour growth and neoangiogenesis. Several recent studies, including work by Baosheng Ren (The Second People’s Hospital of Changzhou, Changzhou, China), Wansheng Wang (The First Affiliated Hospital of Soochow University, Suzhou, China) et al in the Journal of Cancer, have reported that overall survival is improved in HCC patients when treated with a combination of sorafenib and TACE compared with TACE alone.

“But when sorafenib is administered systemically”, White explained, “which is done in order to get high enough levels of the drug into the tumour, it can cause extreme side effects.”

In an effort to eliminate these side effects, nanoparticles can be used to deliver sorafenib locally, rather than systemically. According to White, it is possible to make a nanoconstruct with sorafenib that will deliver and deposit the drug straight to the tumour. White and collaborators have fabricated poly(lactide-co-glycolide) microspheres for local sorafenib delivery to tumours during liver-directed embolotherapies.

These constructs co-encapsulated iron

Sarah White presenting at SIO 2019

oxide nanoparticles (IONP) so that the investigators could observe microsphere delivery via magnetic resonance imaging (MRI). Following intra-arterial microsphere infusions in a rabbit VX2 liver model, White demonstrated in 2015 that these sorafenib particles normalised VEGF activity and decreased microvessel density. Writing at the time in Biomaterials, she concluded “These methods should avoid systemic toxicities, with MRI permitting follow-up confirmation of microsphere delivery to the targeted liver tumors”.

A second clinical application of nanoparticles in interventional oncology is to expand the ablation zone when treating patients with metastatic colon cancer who are not candidates for resection. The ablation zone is limited by size (4mm being approximately the largest possible size) and location (due to the risk of damage to adjacent structures).

Using a rat model of colorectal liver metastases, White and colleagues compared the size of ablation zones in three groups—rats injected with hybrid magnetic gold nanoparticles tagged with monoclonal antibodies, rats injected with hybrid magnetic gold nanoparticles only, and a control group.

After undergoing photothermal ablation with a fibre-coupled near infrared diode laser, haematoxylin-eosin staining revealed a significant difference in tumour necrosis across the three groups.

In the antibody and nanoparticles group, tumour necrosis was 38%±29. In contrast, tumour necrosis in the nanoparticles only group was 14%±17, demonstrating a lack of toxicity. The control group, which were only injected with the colorectal liver metastasis cell lines, had a tumour necrosis of 7%±8 (p=0.043). The addition of the monoclonal antibodies to the nanoparticles also resulted in statistically significant higher levels of delivery to the tumour compared to nanoparticles alone. Published in Radiology in 2017, the investigators concluded that targeted monoclonal antibody–conjugated hybrid magnetic gold nanoparticles can serve as a catalyst for photothermal ablation of colorectal liver metastases by increasing ablation zones.

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Ablation

September 2019 | Issue 75

Cryoablation improves survival more than thermal ablation for renal cell carcinoma patients Cryoablation may be associated with longer overall survival than heat-based thermal ablation in clinical T1a renal cell carcinoma (RCC), concludes a recent study published in the Journal of Vascular Interventional Radiology (JVIR). To date, this is the largest study comparing overall survival between two ablative therapies in these patients.

“FURTHER RESEARCH WITH the use of randomised controlled trials or retrospective studies, with more details on technologies, local outcomes, and complications, is required to identify patients best suited to treatment with either approach”, the authors recommend.

Jing Wu (Central South University, Changsha, China) et al note that a clinical trial comparing the effectiveness of cryoablation with thermal ablation is “not likely to be developed or completed”, and thus set out to assess the survival outcomes of these two treatment modalities using the US’ National Cancer Database (NCDB). Established in 1989, this is a clinical oncology database of hospital registry data gathered from more than

1,500 Commission on Cancer-accredited facilities and sponsored by the American College of Surgeons and the American Cancer Society. Over 70% of newly diagnosed cancer cases in the USA are captured by NCDB data.

A total 6,258 patients who received either cryoablation (3,936 patients) or thermal ablation (2,322 patients) between 2004 and 2014 were included in the study.

The three-, five-, and ten-year survival rates were, respectively, 91%, 82%, and 62% for cryoablation and 89%, 81%, 55% for heat-based thermal ablation. Wu and colleagues report that patients treated with cryoablation had more comorbidities that those treated with thermal ablation. They say that this finding “supports previous

First-in-man study of roboticallyassisted sonic therapy finds the technique safe to plan ablation Preliminary results of a first-in-man trial demonstrate that robotically-assisted sonic therapy (RAST) can create a planned ablation volume without significant devicerelated adverse events. Timothy Ziemlewicz (University of Wisconsin School of Medicine and Public Health, Madison, USA) informed delegates at the 2019 annual meeting of the Society of Interventional Oncology (SIO; 7–11 June, Boston, USA) that short-term local tumour control with RAST may be similar to that of other ablation modalities.

T

he study investigators conducted a phase I trial with the aim of evaluating the safety and shortterm efficacy of RAST for hepatic ablation in patients with primary or metastatic liver cancer. RAST is the automated treatment of a defined volume of tissue utilising histotripsy, the first non-thermal, non-ionizing, non-invasive ablation modality. Prior to this research, RAST had successfully been applied in pre-clinical porcine liver models.

When delineating the advantages of RAST, Ziemlewicz emphasised the precision, telling the SIO audience that the cavitation bubble cloud is precise at the histologic level (“so you can literally cut cells in half with it”), and that planned treatment volumes are within

studies suggesting heat-based thermal ablation as [sic] less effective in managing larger masses”.

Detailing their results, the authors write: “On univariate Cox regression analysis, compared with cryoablation, the hazard

RCC ablation

of mortality was increased for patients treated with heat-based thermal ablation (p=0.031). On multivariate Cox regression analyses adjusted for age, facility type, facility location, insurance status, education level, income, residence, CharlsonDeyo score, tumour size, and treatment, cryoablation remained associated with longer overall survival compared with heatbased thermal ablation (p=0.021).”

This difference in overall survival was only apparent in tumours larger than 2cm, according to the investigators. The authors say: “This is in accordance with a previous retrospective study of 445 patients that demonstrated similar outcomes between cryoablation and heat-based thermal ablation when treating masses ≤3cm”.

Centre and experience were not found to have an effect on overall survival. “In

nanometres of the resultant ablation.

The phase I, open-label, non-randomised trial had a primary endpoint of technical success, defined as the ability to create an ablation zone per the planned volume, as assessed by MRI one-day post-procedure. There were multiple secondary endpoints, the most important of which, according to Ziemlewicz, was safety, measured as the number and severity of adverse events. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0), a descriptive scale from Grade 1 (mild) through to Grade 5 (death related to adverse event). The study investigators also evaluated local tumour progression, liver function, involution of the ablation zone, and analgesic requirements. Follow-up MRI, laboratory draws, and clinical visit were planned at one day, one week, one month, and two months.

Eight patients (five female, three male) have had a tumour treated under this protocol. Most patients (six) had a single tumour, one patient had two tumours, and one patient had three tumours. The mean tumour size was 1.3cm, and the range was 0.5cm to 2.3cm. “We were somewhat limited in size by having to fit treatments within livers with multifocal tumours”, Ziemlewicz said.

The trialists achieved 100% technical success in creating the planned ablation volume using RAST. In the axial plane, the ablation zone was within an average of 0.1cm of the plan, and in the coronal plan the ablation zone was an average of 0.5cm larger than the plan. “We did not control for respiration”, Ziemlewicz commented, “so we knew that these would be elongated in the coronal plane”. In terms of targeting tumours, the investigators report a 90.9% success rate—one of the eleven tumours treated was mistargeted immediately adjacent to the 0.5cm tumour. Ziemlewicz ascribed this mistargeting to poor ultrasound visualisation, and explained that the patient is set to undergo a second procedure for local control.

Concerning safety, there was one Grade 4 adverse event (classified as life-threatening, with urgent intervention indicated), which Ziemlewicz explained was not thought to be device-related. The patient was admitted to hospital and the complication was attributed by the independent

fact”, the authors write, “patients who went to facilities reporting ≥100 cases over the past 10 years had shorter survival than those who went to facilities reporting <100 cases”. They posit that this difference in survival is due to the fact that patients were sicker in the more experienced centres, as large academic centres take complex cases where patients are more likely to have increased comorbidities.

Another explanation the authors suggest is that “with high-volume centres reporting more heat-based thermal ablations than cryoablations, the shorter survival may be related to the shorter survival associated with the procedure itself”.

The study authors describe ablation as “a nephron-sparing minimally invasive approach that is typically used for patients who are not optimal surgical candidates or who have masses within a solitary functioning kidney or in association with renal dysfunction”. They explain that, although partial nephrectomy “remains the most common treatment for clinical T1a RCC, ablative therapies serve as a less invasive alternative and offer distinct advantages in both complications rate and cost-effectiveness”.

Being retrospective, Wu et al say that the potential for selection bias “must be considered”. Also, the study only reports on overall survival, not cancer-specific survival, “which would be expected to have more direct implications on treatment consideration”.

treating physicians to their underlying Crohn’s disease.

In addition, there was one Grade 2 (designated as a moderate complication) adverse event, which was also not attributed to the device. This patient was admitted to hospital for fever and given supportive treatment. One patient had a complication that was device-related; a Grade 1 (mild) adverse event, they presented with postablation syndrome one day after the procedure and had a fever of 39°C. This patient was the only one of the eight to have three ablative treatments; 64mL of total ablation.

“They had a fever and some malaise for a couple of days after the procedure, which resolved and they are doing fine [now]”, Ziemlewicz assured the audience.

The deepest tumour treated by the study investigators did experience some local progression. Explaining this, Ziemlewicz said: “The prototype transducer we used is only capable of treating to about 10cm; we were pushing it to the edge of the envelope [with trying to treat this tumour].” Showing the audience some post-procedural images of the patient’s liver, he commented “You can see at one month the ablation zone is nicely absorbed, and then at the three-month follow-up scan you can see the progression. One of the benefits of this technology is that you can see this relatively early.”

The involution data were of particular interest to the investigators as they were unsure how this would translate from previous laboratory studies. There was significant involution after two months: an average of 88.1% volume contraction and 51.1% diameter contraction. Ziemlewicz suggested that rapid involution may allow earlier identification of incomplete treatment.

All RAST procedures (VORTX RX system, Histosonics) were performed with the patient under general anaesthesia. Ziemlewicz said that, initially, the investigators did not know how the patients were going to feel, and so stayed consistent with their institution’s policy of using general anaesthetic for all ablation patients. He did say, though, that “Anecdotally, none of the patients showed any vital sign changes to suggest they were having pain during the procedure. In the future, we will definitely consider doing this with conscious sedation”.

Radiofrequency ablation

Issue 75 | September 2019 ADVERTORIAL SPONSORED BY MEDTRONIC

OsteoCool™ radiofrequency ablation for painful bone tumours The OsteoCool™ radiofrequency ablation system (Medtronic) can be used for palliative treatment of bone metastases and benign bone tumours. Here, MK Jesse describes a case where the system reduced the patients’ pain score, thereby improving quality of life.

Introduction

The metastatic lesion in this case lies along the margin of the sacroiliac joint. Tumour involvement of bone adjacent to the sacroiliac joint is particularly painful due to the local inflammatory effects at a mobile segment. OsteoCool™ radiofrequency ablation (RFA) is a reasonable option for this tumour given the absence of any adjacent critical structures. The vicinity of the sacroiliac joint cartilage did not preclude RFA therapy. Histopathologic studies have demonstrated no significant alteration in cartilage architecture following RFA (Vinkingstad et al, Comparison of acute histologic and biomechanical effects of radiofrequency ablation and cryoablation on periarticular structures in a swine model, JVIR 2015).

Patient history

■ 52-year-old female with metastatic breast cancer.

■ 8/10 non-radiating pain to the posterior right iliac region, as measured by the visual analogue scale (VAS) for pain.

■ Pain was at maximum during prolonged ambulation.

and two single probes to cover cranial and caudal extension.

Discussion

The patient experienced near complete pain relief, with a post-operative VAS score of 2/10 one-week after the procedure. A delay in pain relief of three to 10 days is typical for extra-spinal cases in which there is no pathologic fracture. Post-procedure pain is often

increased as the extraosseous/soft tissue ablation zone increases. The immediate post procedure inflammatory phase can be mitigated by antiinflammatories. Lesions adjacent to the sacroiliac joints are often painful and are good candidates for percutaneous ablation.

Extra-spinal areas MK Jesse particularly amenable to this therapy include the periarticular and supra-acetabular iliac crest, posterior iliac crest, sacrum, ribs and scapula. A keen understanding of nerve anatomy in these areas is critical to avoid complications and improve patient outcomes.

MK Jesse is an associate professor of Radiology at the University of Colorado Hospital, Aurora, USA.

Indications and risks A

Procedural goals and approach

We desired full tumour coverage in this case to ensure ablation of all bone tumour interfaces. We therefore placed four 20mm probes: parallel placement of two probes at the maximum transverse width of the lesion

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C

B A: Axial CT shows lytic lesion in the posterior right iliac crest abutting the sacroiliac joint.

B: I ntra-procedural CT of parallel probe placement.

C: A xial T1 post contrast MR at three months post procedure demonstrates notable decrease in size of the extra-osseous component.

The OsteoCool™ RF Ablation System is intended for ablation of benign bone tumors such as osteoid osteoma and the palliative treatment in spinal procedures by ablation of metastatic malignant lesions in a vertebral body. It is also intended for coagulation and ablation of tissue in bone during surgical procedures, including palliation of pain associated with metastatic lesions involving bone in patients who have failed or are not candidates for standard therapy. Risks of the system include damage to surrounding tissue through iatrogenic injury as a consequence of electrosurgery and pulmonary embolism.

Customer service: (001) (800) 933-2635

Physician burnout

Issue 75 | September 2019

Over 70% of interventional radiologists polled experience career burnout

Burnout is prevalent among interventional radiologists, with a recent survey finding that both identifying as female and working more than 80 hours per week are significantly associated with high emotional exhaustion and depersonalisation (p=0.009 and p=0.030, respectively).

THE SURVEY RESULTS were published in the Journal of Vascular and Interventional Radiology by joint first authors Jacob Bundy (Department of Radiology, University of Michigan Health System, Ann Arbor, USA) and Anthony Hage (Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, USA) et al.

Aiming to assess the prevalence of burnout and to determine demographic and practice-related stressors among interventional radiologists, Bundy, Hage and colleagues posted a 34-question survey to the Society of Interventional Radiology (SIR) Connect Open Forum website, which on the day of posting (7 January 2019) had 7,402 members. From the total membership, there were 339 complete responses. The prevalence of burnout was 71.9% (244 respondents).

This abundance of burnout places interventional radiologists in the upper range of that reported amongst all medical specialties. The prevalence of this condition in medicine as described in the literature varies from 30–75%. In fact, the authors write, “Interventional radiologists report manifestations of burnout at a rate higher than not only the general public (28%) but also diagnostic radiologists (54–61%) and surgeons (40%)”.

Bundy, Hage et al believe that the survey answers “indicate that additional harmful external factors exist and may require attention when combating burnout among interventional radiologists”. Highlighting perceived gender stereotypes, bureaucracy and administrative duties as prominent amongst these external factors, the authors say that these “represent

problems that may not be resolved through established physician wellness programmes, but instead may require human system interventions driven by organisational restructuring and redirection toward patient-centred care rather than financial obligations”.

Interventional radiologists at high risk of emotional exhaustion and depersonalisation

The study authors define burnout as “a cluster of symptoms that occur in response to chronic emotional career-related stressors resulting in emotional exhaustion, depersonalisation, and lack of personal accomplishment in relation to one’s professional activity”. It was evaluated using the 22-item Maslach Burnout Inventory-Human Services Survey (MBI) for Medical Personnel (Mind Garden). Additionally, the survey included 10 demographic questions, ascertaining age, gender, current level of practice, time since fellowship training, practice setting, number of interventional radiologists in the practice, daily percentage of time spent performing nonprocedural diagnostic radiology, mean weekly hours worked, presence of interventional radiology (IR) call duties, and mean number of call shifts taken per month. An optional, open-ended, free response question regarding the greatest contributor to burnout in the workplace was also included.

A total of 61.9% of responders were at high risk of emotional exhaustion, according to the MBI subscales.

A further 15.3% were at a moderate risk, and the remaining 22.7% were low risk. The mean MBI

The questionnaire used to survey burnout amongst interventional radiologists

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score for emotional exhaustion was 30±13, which is categorised as high (low ≤18; moderate 19–26; high ≥27). The mean depersonalisation score was also high, at 10.6±6.9 (low ≤5; moderate 6–9; high ≥ 10). Just over half of survey respondents—54.3%—were at high risk of depersonalisation. An additional 17.2% were at a moderate risk, and 28.6% were low risk. One-hundredand-sixty-two (47.8%) responders were at high risk of both depersonalisation and emotional exhaustion.

“Personal achievement scores were high in only 14.7%” of respondents, the authors write. Personal achievement ranking was not used to determine if a participant had burnout. Most responders (59.3%) reported low personal achievement, and 26% reported a moderate personal achievement rating. However, the mean personal achievement rating was 39.6±6.6, just shy of a “high” designation (low ≥40, moderate 34–39, high ≤ 33).

Explaining the open-ended responses received, which were given by 258 survey participants (76.1%), the authors say: “On review of the responses, several themes emerged, including administrative pressures on productivity and administrative tasks, relationships between interventional radiologists and ancillary staff, workload and work hours, electronic medical record and documentations systems, diagnostic radiology responsibilities, contentious relationships with diagnostic radiologists within the same practice, lack of recognition and respect from other medical and surgical subspecialties, and fielding inappropriate consultations from other medical professionals”.

Bundy, Hage et al express concern at their finding, continuing: “The technical challenges, physical demands, and unpredictable work hours of IR likely impart different stressors [to those experienced by other medical specialties, such as diagnostic radiology], and thus rates of burnout may be related to these factors. Regardless, this is an alarming finding given the negative impact burnout has on job satisfaction, career longevity, mental health, and patient care”.

Female interventional radiologists are more likely to experience burnout than male physicians

Gender was significantly associated with increased rates of burnout, with women having 2.4 times’ higher odds of experiencing burnout than men. The study authors say that “Gender judgement and stereotypic perceptions of female physicians have been linked to increased rates of burnout and worsened psychological well-being”. To remedy this, Bundy, Hage and colleagues suggest that increasing the number of women in the male-dominated discipline of interventional radiology “may mitigate the relationship between stereotypic perceptions and burnout among women”.

That women have an increased propensity to work more than 80 hours a week compared with their male counterparts is also potentially a contributing factor to their higher incidence of burnout, according to the study investigators. Interventional radiologists who worked more than 80 hours per week were seven times more likely to report traits indicative of burnout than those who worked fewer than 80 hours in a week.

“Of note”, the authors write, “the form of call taken in the present survey was not assessed; however, IR call shifts would likely contribute differently than diagnostic radiology call shifts toward the total hours worked”. They continue, “Whereas physician expectations for acceptable work hours vary by specialty, a dependent response is likely present between work hours and burnout. Although not an easily applicable intervention, decreasing work hours or other contributors to overall workload may have a substantial impact on lowering the incidence of burnout amongst interventional radiologists”.

The authors also note that, despite the fact that the survey was intended to capture a representative cross section of interventional radiologists in training and practice, respondents were disproportionately early career physicians. They suggest additional analyses of burnout within age-specific subsets of IR physicians and trainees to “further delineate the aetiologies of burnout among these groups”.

Physician burnout

Issue 75 | September 2019

Burning out: A woman physician’s experience Sasha Shillcutt Comment & Analysis Following a keynote lecture on her personal and professional understanding of physician burnout earlier this year at the annual meeting of the Society of Interventional Radiology (SIR; 23–28 March, Austin, USA), Sasha Shillcutt here details the changes physicians can make to best achieve “work/life integration”, emphasising the importance of not compartmentalising yourself.

I

was approaching 24 hours in the hospital and waiting for my partner to come into my operating room so we could do “hand-off”, where I spend 15 minutes going over all of the events of the surgical case and explain my patient’s health history, his current status, my current treatment strategies, the echocardiography findings, and our plan for the rest of the case. As I was awaiting my colleague’s arrival, I received a text from my son, AP. AP: We need to make lunches, when will you be home? Are you taking us to school?

Me: Please make sure everyone is awake and make lunches.

AP: S2 is still asleep. He’s refusing to wake up.

Me: Can you PLEASE wake him up and make lunches. Also, get the papers on the island ready to hand in—they were there two nights ago.

Two nights ago, the last time I was awake in my house.

In comes my partner, and we chat.

I tell him about my last 24 hours and the patient in my care. We review the anaesthesia record and the current surgical state. I say goodbye to the surgeon, the third one I have worked with in 24 hours. He thanks me for my help through the night and wishes me a good day.

I do a five-minute change and rush home, transitioning into mum mode.

I call home on the way and put out sibling fires and rally the sleepy preteen over the phone. When I arrive, AP has delivered: everyone is dressed, breakfasted, and lunches are thrown in backpacks. I kiss everyone hello and tell them I have missed them. I drive them to school and hear about yesterday’s events and today’s plans.

They exit the car and I kiss them again.

A little pang goes off in my heart; I just said hello, and now I am saying goodbye.

When I finally get home, I try and decide: sleep, shower, or coffee? And

in what order? Should I empty the dishwasher, go through the mail, or just ignore it until later? Should I catch up on emails, or crash into a few hours of sleep? Should I run errands? After all, I am awake.

This is a very typical day in my life, and in most physicians’ lives. I recognise this does not just happen to doctors, it happens to many of us who work in areas such as healthcare, emergency service personnel, military, and law enforcement. We feel honoured to care for other’s sisters and dads and brothers and friends; yet we are all of those things to others, and find it a difficult balance.

In the last two years, out of complete

would not think I was serious about my job because I am a woman “mumming” at work. I stopped trying to hide in my bedroom to answer a consult at home. I just embraced that I was both of those things, and people who respected me would have to as well.

Burnout, in any profession, will steal your empathy and your innovation and, well, YOU. You will feel less engaged, less motivated, physically and emotionally exhausted, and start to withdraw. It is a dangerous path and can lead to very costly problems for individuals, institutions, and your family. Over 50% of physicians report burnout, and the suicide rate is 1.5–2.3x higher in male and female physicians than the general population.

This is a real problem.

For me, when I started embracing that my work would flow into home and my home would flow into work, suddenly my work became much more manageable. Now, do I answer questions about homework during an emergency at work? Of course not.

Do I answer phone calls from work when my son is about to take a penalty kick? Heck no, I am cheering on the sidelines and it can wait 10 minutes.

Do I have best friends who I also work with that I meet and have coffee with and decompress about a case that I am struggling to let go of? Absolutely. Do I invite my mother to hear me speak professionally, so she can understand what I do? Absolutely. Do I write manuscripts on the sidelines of my son’s football practice when I have down time? Of course.

I am both doctor and mother. It is important to leave work and be a sister, a friend and a dad. It is important to shut down devices and decompress and connect with your loved ones. I am

Five years ago, I experienced clinical burnout myself and nearly quit the practice of medicine. Despite years of training and practice, I did not want to be a cardiac anaesthesiologist anymore. I knew I was in danger.” necessity, I have studied professional burnout. Five years ago, I experienced clinical burnout myself and nearly quit the practice of medicine. Despite years of training and experience, I did not want to be a cardiac anaesthesiologist anymore. I knew I was in danger.

I needed to get a handle of my work/life integration. I do not use the term “work/life balance” anymore; I recognise that the 10-year quest for “balance” left me empty, defeated and more stressed than ever. So this is what I did: I embraced the suck.

Literally and figuratively. I stopped trying to be a “doctor” at work and a “mother” at home. I am both, all the time, and they are integrated. I stopped worrying that if I talked to my son about his homework over the phone at work and someone heard me they

not promoting a 24/7 work life. I am promoting embracing the fact you are ONE. One person, who is many things.

And it is OK to be all of yourself, at all times. My patients and my work colleagues deserve my BEST self; that person is a mum, a wife, and a friend.

And what I have found is that I have

Sasha Shillcutt

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developed resilience and respect from my colleagues by being fully ME. When I speak professionally on burnout and overcoming professional failure, I encourage physicians and leaders to make these changes:

1. Set boundaries.

When we are burned out, we must pull back from what we are being asked to do (or over-asked to do) and have frank conversations with leadership and say enough. There are limits to what we can do in a day, and we need leaders who listen to our requests for support; whether it is clerical, administrative, or procedural.

2.Start with one efficiency fix.

Identify the area of your workflow that is most problematic and requires you to do things inefficiently or takes your time and steals your joy. If you can recruit stakeholders to make changes, and fix one problem at a time, you will immediately see improvements.

3. Stop judging yourself for being burned out.

Start allowing yourself space to work on your own wellbeing. This is often hard for us as we care for others, we work incredibly long hours, and we feel guilty saying no to extra work. Here is the thing: the hardest working people burnout the most. Give yourself grace to recognise this, and empower yourself to say yes to your own health. Only you know what you need to be mentally and physically healthy—it is different for each individual.

4. Plan your wellbeing.

Wellbeing must be intentional.

Wellness is not doing yoga, it is living within healthy boundaries you set for yourself and finding joy in your personal and professional life. Allow yourself to be a whole person—both at work and at home, and understand that requires saying no, thank you. And it may require change.

Let us stop judging one another in healthcare; rather, let us encourage each other to be our whole selves; not half and half. Whole. It is where freedom lives.

Sasha Shillcutt is a professor and the vice chair of Strategy and Innovation in the Department of Anesthesiology at the University of Nebraska Medical Center (UNMC; Omaha, USA). She leads conferences and retreats for women through her organisation, Brave Enough.

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Interview

September 2019 | Issue 75

Profile

Konstantinos Katsanos Following the publication of a meta-analysis in the Journal of the American Heart Association late last year that reported an increased association of mortality with paclitaxel devices used in the leg, Konstantinos Katsanos found himself at the centre of a maelstrom of debate and division within the international endovascular community. Here, he discusses that spotlight on his science, as well as enthuses about the future of vascular access and interventional radiology as a whole, which he imagines will ultimately become needleless.

Why were you initially drawn to interventional radiology?

I was just about to finish my undergraduate studies at the Patras School of Medicine in 2001 when I was exposed to a peripheral Angiojet thrombectomy case that was the first one to be performed in Europe, by professor Dimitris Siablis. I still remember my fascination with the specific medical device fragmenting and aspirating the thrombus through remote pinhole access in the groin—being a medical student at the time, the sheer potential of catheter-based technologies was mind boggling to say the least. Over the next couple of years, I slowly became addicted to the field of interventional radiology (IR) and image-guided therapies in general through attending national and international symposia (including CIRSE [the annual meeting of the Cardiovascular and Interventional Radiology Society of Europe]) that confirmed in my eyes the transformational and cutting-edge character of IR.

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

Nowadays, I most enjoy combining general clinical skills with image interpretation and image guidance to deliver highly accurate therapies with the use of sophisticated catheters and dedicated miniaturised medical instruments. Transcatheter atherectomy for plaque excision/removal, the use of drug-coated balloons and stents for the inhibition of vascular restenosis, utilising radioactive beads for targeted internal organ radiation therapy, balloon kyphoplasty and new-generation vertebral augmentation techniques are some of my favourite procedures—all of which demonstrate the unique, minimally invasive, and highly effective nature of IR treatments.

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

Professor Dimitris Siablis has been my IR teacher and mentor from the very beginning. He had the courage to believe in me whilst I was still an undergraduate student, invested his time in teaching me most catheter and guidewire skills, and had the kindness to mentor me through my early academic endeavours. He has actually been more of a coach and mentor then a professor of medicine. His ‘inheritor’ and my current director, professor Dimitris Karnabatidis, has continued the tradition by delivering unlimited, unselfish and considerate education and guidance not only to myself, but to a whole team of more than a handful aspiring junior IR fellows. Finally, Professor Andreas (Andy) Adam, who was my director for nearly five years at St Thomas’ Hospital in London, UK, has been a unique role model by exhibiting exemplary leadership and sharing unparalleled insights into the future of the IR profession.

Having worked in both Greece and the UK, what are the similarities and differences between these two healthcare systems for interventional radiologists?

I have been very fortunate to work in two completely different healthcare systems both as a trainee/fellow and as a consultant/professor. Greece has been the stepping stone in my early training days in IR and the UK has been the landing site for my junior consultant job. I was lucky to enjoy the benefits of the more liberal, more forgiving Greek healthcare system early on followed by the more mature and conservative UK National Health Service later as I was transitioning to a consultant level job with different priorities and responsibilities. I think that in a combined way they both contributed to my education by amalgamating current standards of clinical practice, academic research and medical ethics.

Late last year, you published a paper in the Journal of the American Heart Association (JAHA) that reported an increased mortality with paclitaxel devices in the femoropopliteal arteries.

How do you see these findings changing practice in the future?

By employing good research and statistical practice, we showed that there is increased risk of all-cause patient death with the use of paclitaxel-coated balloons and stents in the femoropopliteal artery in the lower limbs for treatment of intermittent claudication.

Interestingly, since our contentious publication in JAHA, two companies have produced errata of mortality counts in industry-sponsored studies. Meanwhile, new evidence has also come to light, mostly in the form of so-called individual patient data (IPD). Both the IPD analysis performed by the US Food and Drug Administration (FDA) and the one performed by the non-profit VIVA consortium have confirmed a significant mortality risk with the use of paclitaxel (when analysing the data from the pivotal randomised controlled clinical trials). I personally maintain the view that the future of endovascular peripheral arterial disease (PAD) treatments is going to be drug-coated or drug-eluting, but in a different way. As I have stated before, endovascular treatment is not going back to the Stone Age of plain balloons and metal any time soon. I personally think that had there been an alternative means (other than paclitaxel) to treat restenosis, we would not have had the kind of intense reaction we experienced.

How has your life changed as a result of publishing research that is not positive, and how have your coped with the reaction from the medical community to the JAHA paper specifically?

Our findings have initially been received with anger and denial—often regrettably so by our own peers. However, we are scientists and we need to read the numbers, apply good statistical practice and acknowledge and act on the results regardless of personal, commercial, emotional or other conflicts of interest. The fact that paclitaxel is the only difference in the treatment between active and control arms across all randomised controlled studies makes it very likely that paclitaxel is also the cause of the problem—in a direct or indirect way. This is not to say that we definitively know that paclitaxel causes the

We have the responsibility to report both positive and negative findings to be able to advance science for the sake of patient safety and public health.” problem. Ultimately, we have the responsibility to report both positive and negative findings to be able to advance science for the sake of patient safety and public health.

To quote Sir Bradford Hill in his 1965’s presidential address: “All scientific work is incomplete—whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge.

That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action

Interview

Issue 75 | September 2019

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Fact File

You hosted the first ever EndoVascular Access (EVA) meeting this year with Panagiotis Kitrou and Dimitrios Karnabatidis.

What are your ambitions for this meeting, and how do you hope to see this field develop?

Our aim has been to create a meeting fully dedicated to the emerging role of endovascular management of dialysis access. EVA encompasses topics from access creation (surgical or endovascular) to percutaneous maintenance and declotting by treatment of stenoses and thromboses.

EVA will strive to disseminate the highest quality of relevant medical research and increase awareness among healthcare professionals on the important service they can provide to their dialysis patients by increase access longevity and improving quality of life. This is extremely important as we strongly believe that the future of dialysis access is endovascular.

We envision that EVA will soon become the go-to meeting of reference in the field of endovascular access interventions.

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

that it appears to demand at a given time.” Being in the spotlight should not disrupt or affect in any way solid, credible scientific research.

How do you feel the regulatory bodies across the world have responded to the mortality signal reported in your publication?

I think that regulatory bodies across the world (the FDA, the Medicines and Healthcare products Regulatory Agency [MHRA], etc.) have responded swiftly, responsibly and above all professionally in validating our findings and interacting with the industry to guide next steps. On their mandate, industry stakeholders have quickly collected and delivered a wealth of new data in order to better understand this alarming situation.

Unfortunately, however, in my personal opinion it is a real shame that the average researcher or scientist is not allowed access to all that individual patient data for more in-depth analyses and explorations of alternative hypotheses.

I am currently predicting/dreaming of augmented reality in the IR suite for improved perception and manual skills, routine use of perfusion monitors for diagnosis and aftercare of critical limb ischaemia, multi-drugcoated balloons for angioplasty and multichemo-laden microparticles for cancer embolization, integration of optics and photonics for the design of next-generation needles and catheters, and most likely the gradual emergence of completely needleless procedures, for example high-intensity focused ultrasound ablation of a tumour or magnetically guided microparticles to concentrate into particular tissue sites or intravascular micro-robots harnessing energy from the host to propel themselves and clear the arteries and/or deliver medications on demand.

What are your hobbies and interests outside of medicine?

My hobbies outside of medicine are: movies, computers and tech, occasionally running and cycling. Personal interests beyond academia include European and global geopolitics, space exploration and an ongoing fascination with numbers and maths.

Current positions

2016–Present: Assistant professor in Interventional Radiology, Patras University Hospital, School of Medicine, Patras, Greece 2016–Present: Honourary consultant in Interventional Radiology at Guy’s and St Thomas’ Hospitals, King’s Health Partners, London, UK 2010–Present: Lecturer, Radiology, Patras University Hospital, School of Medicine, Patras, Greece

Previous positions

2012–2016: Consultant interventional radiologist, Guy’s and St Thomas’ Hospitals, NHS Foundation Trust, London, UK 2008–2009: Senior Registrar, Diagnostic and Interventional Radiology, Health Sciences Division, Patras University Hospital, School of Medicine, Patras, Greece

Education 2003–2009: PhD candidate, Laboratory

of Pharmacology, Health

Sciences Division, School of

Medicine, University of

Patras, Patras, Greece 2008: Subspecialty fellowship, Interventional Radiology, Guy’s and St Thomas’ Hospitals, London, UK 2006: MSc, Pharmacology and

Pharmacokinetics, School

of Medicine, University of

Patras, Patras, Greece

Honours and awards (selected) 2015:

2014:

hortlisted finalist in the S Imaging category, National BMJ awards Certificate of Merit, Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting, for the presentation “Drug-eluting stent placement in the bifurcation and trifurcation of the tibial arteries: How I do it”

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Paclitaxel

September 2019 | Issue 75

FDA: Paclitaxel device clinical trials “may continue”; Agency is working to change informed consent documents and product labelling

Clinical studies of paclitaxel-coated balloons and paclitaxel-eluting stents “may continue and should collect long-term safety (including mortality) and effectiveness data”, says the US Food and Drug Administration (FDA) in a letter to healthcare providers on 7 August.

This is due to “the demonstrated short-term benefits of the devices, the limitations of the available data, and uncertainty regarding the long-term benefit-risk profile of paclitaxel-coated devices”.

T

he letter provides an update on the agency’s stance on the use of paclitaxel devices to treat peripheral arterial disease (PAD) in the femoropopliteal arteries. The FDA says clinical studies investigating these devices in the lower leg “require appropriate informed consent and close safety monitoring to protect enrolled patients”, and confirms they are working with study investigators to modify informed consent documents to include information about the late mortality signal.

The FDA states: “Based on the conclusions of our analysis and recommendations of the advisory panel, the FDA is taking additional steps to address this signal, including working with manufacturers on updates to device labelling and clinical trial informed consent documents to incorporate information about the late mortality signal. The FDA is also continuing to actively work with the manufacturers and investigators on additional clinical evidence development for assessment of the long-term safety of paclitaxel-coated devices.”

physicians should explore their patients‘ expectations, concerns and treatment preferences.

Ensure patients receive optimal medical therapy for PAD and other cardiovascular risk factors as well as guidance on healthy lifestyles including weight control, smoking cessation, and exercise.

Report any adverse events or suspected adverse events experienced with the use of paclitaxel-coated balloons and paclitaxel-eluting stents. Voluntary reports can be submitted through MedWatch, the

development to assess the long-term safety of paclitaxel-coated devices.

Analyses of additional randomised trials and registry datasets are being planned to provide further insights into the magnitude and potential causes of the late mortality risk.

The FDA is working with manufacturers on labelling updates for paclitaxel-coated devices to include information about the late mortality signal.

For ongoing trials of paclitaxelcoated devices, the FDA is working with study investigators to modify informed consent documents to include information about the late mortality signal.

Meta-analysis finds a higher risk of death in the long term when paclitaxel-coated devices are used in the leg

The publication of a meta-analysis in the Journal of the American Heart Association (JAHA) on 6 December 2018 sparked an international controversy over the use of paclitaxel devices, after Konstantinos Katsanos (Patras, Greece) and colleagues concluded that there was an increased association of mortality at five years when these products were used to treat PAD in the femoropopliteal arteries (see page 30).

stents used to treated PAD in the femoropopliteal arteries.

Following the two-day discussion, which included the presentation of the agency’s own analysis of long-term follow-up data from pivotal premarket randomised trials, an FDA Circulatory System Devices Panel Advisory Committee concluded that there is a “late mortality signal”, as first described in the JAHA paper authored by Katsanos et al in December 2018.

However, they also concluded that better data collection was necessary going forward, as some data were missing, a small sample size meant there were wide confidence intervals, and there was pooling of studies of different paclitaxel devices that were not intended to be combined. The panel determined that there were not enough data to confirm a class effect, and no consensus was reached on the cause(s) of death.

“One of the take-aways from this has been that in this field of lower extremity revascularisation, the quality of these data and the rigour of these clinical trials has been somewhat amiss, that even with the adjustments in follow-up, anywhere from 6% to 26% of the patients’ data are missing at one and five-year follow-up,” surmised Todd Rasmussen, a vascular surgeon in Kansas, USA. On the second day, themes of the

The recent FDA’s recommendations

In full, the recommendations from the FDA on 7 August are: Continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents.

When making treatment recommendations, and as part of the informed consent process, consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.

Discuss the risks and benefits of all available PAD treatment options with your patients. For many patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents provide a more favourable benefit-risk profile based on currently available information.

For individual patients judged to be at a particularly high risk of restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxelcoated device outweigh the risk of late mortality.

In discussing treatment options,

Misti Malone at the CX Symposium 2019

FDA Safety Information and Adverse Event Reporting programme. Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations.

Health care personnel employed by facilities that are subject to the FDA‘s user facility reporting requirements should follow the reporting procedures established by their facilities. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.

FDA actions

In full, the FDA actions are: The FDA continues to work with the manufacturers and investigators on additional clinical evidence

Writing at the time, Katsanos et al said that the meta-analysis provided good statistical evidence to back its findings, but some leading physicians stated that it lacked individual patient-level data from the randomised controlled trials.

The quest for individual patient-level data is ongoing, though earlier this year several manufacturers released their own patient-level analyses, which reported no increased mortality with these devices.

Summary of earlier FDA statements

In June this year, the agency convened a Circulatory Systems Devices Panel meeting (19–20 June, Washington, DC, USA) on the late mortality safety signal associated with paclitaxelcoated balloons and paclitaxel-eluting

meeting included the risk-benefit consideration for patients, and how best to convey the choice of paclitaxel treatment in the context of short-term benefit and improved quality of life weighed against a signal of late mortality risk. The panel largely agreed that patient choice is central, as clinical benefits are clearly demonstrated and increased quality-of-life may be an acceptable trade-off for long-term risks for many patients.

Furthermore, consistently noted throughout panel discussion was the importance of collaboration between industry, regulatory bodies and other stakeholders to ensure data gaps are filled and strategically tackled.

Recommendations regarding future study designs as well as optimisation of

Paclitaxel

Issue 75 | September 2019 ongoing trials were discussed, with no consensus on the value of registry data as opposed to more time-consuming and expensive randomised controlled trials. However, FDA representative Bram Zuckerman stated in the last hour of the meeting, “Unfortunately, we have a signal here that remains undetermined. One of the reasons why is that the death adjudication uniformly in these FDA trials was poor.” He summarised, “going forward, mortality will be given a higher priority, and we will need to think about how it can be best assessed and adjudicated.”

The panel agreed that in terms of determining efficacy, studies can follow up to one year for these endpoints, while safety should be assessed over a longerterm follow-up of three to five years.

Concluding the meeting, Bram Zuckerberg states that the two-day meeting and presentation has been “extremely helpful” for the FDA, who will now consider the analysis of the panel, and “look forward to continued collaboration in this field.”

In its most recent letter to healthcare providers, dated 7 August 2019, the FDA summarises the deductions of the advisory committee in June: “In the three randomised trials which enrolled a total of 1,090 patients, the crude mortality rate at five years was 19.8% (range 15.9–23.4%) in patients treated with paclitaxel-coated devices compared to 12.7% (range 11.2–14%) in subjects treated with uncoated devices. The relative risk for increased mortality at five years was 1.57 (95% confidence interval 1.16–2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices. A metaanalysis performed by VIVA (Vascular InterVentional Advances) physicians of patient-level data provided by manufacturers reported similar findings with a hazard ratio of 1.38 (95% confidence interval 1.06–1.80). […]

The Panel determined, and the FDA concurs, that additional clinical study data are needed to fully evaluate the late mortality signal.”

MHRA response: Do not use paclitaxel devices in the routine treatment of patients with intermittent claudication

Prior to the Circulatory Systems Devices Panel meeting convened by the FDA in late June, the UK Medicines and Healthcare products Regulatory Agency (MHRA) acted to limit the future use of paclitaxel-eluting stents and paclitaxelcoated balloons in routine clinical care following recommendations from the independent Expert Advisory Group (EAG) on the use of these devices.

The independent EAG was formed following the publication of the Katsanos et al JAHA meta-analysis, and consists of leading UK clinicians from multiple specialties, including interventional radiology, vascular surgery, toxicology and statistics. The group reviewed the findings of the Katsanos et al paper, and concluded that the statistical analysis used by the investigators was robust.

Do not use paclitaxel devices in the routine treatment of patients with intermittent claudication until further notice, the Medical device alert issued by the MHRA announced, “as the potential mortality risk generally outweighs the benefits”. However, the use of DCBs and DESs may still be considered in patients with critical limb ischaemia, taking National Institute of Care Excellence (NICE) guidance into consideration, in view of their increased risk of restenosis and reduced life expectancy, the MDA acceded.

The EAG also considered that “there is a possible dose dependent effect of the use of paclitaxel-coated/-eluting devices on mortality although no scientific or

35

Based on the conclusions of our analysis and recommendations of the advisory panel, the FDA is taking additional steps to address this signal.” clinical explanation is currently available.

“There are some established causal links between multiple factors and mortality, but the association of increased mortality and the use of paclitaxel-coated/-eluting devices is established by randomised controlled trials which control for confounding in known factors. There is no evidence to suggest that confounding persisted

within these studies. Current knowledge gaps include dose-time relationship, outcomes of paclitaxel coated balloons versus paclitaxel eluting stents, patient factors, effect on patients with claudication compared with those with critical limb ischaemia, peer-reviewed publication of commercial evidence, mechanistic explanation, and biological evidence.”

36

Pharmacokinetics

Holden et al find no causal link between paclitaxel dose and all-cause mortality The methodology underpinning the conclusion

by Konstantinos Katsanos (Patras, Greece) et al that there is a positive dose-response relationship between paclitaxel and mortality is flawed, argues Andrew Holden (Auckland, New Zealand) and colleagues in a paper published in the Journal of Endovascular Therapy (JEVT). Holden and co-authors list the limitations they see in the summary level meta-analysis published in December 2018 in the Journal of the American Heart Association (JAHA), and call for physicians to “significantly modify the way vascular device trials are performed in the future”.

IN THE JAHA meta-analysis, Katsanos et al linked paclitaxel-coated balloons and paclitaxel-eluting stents to all-cause mortality, reporting a significant increase in deaths at two and five years in the cohort of femoropopliteal disease patients exposed to the drug compared to those treated who were not. Holden et al write: “Although no plausible mechanism of action was identified, the authors postulated that the excess mortality was caused by paclitaxel”.

However, Holden and colleagues do not find this correlation with paclitaxel levels and mortality, and thus claim there is no causative link between dose and death.

On 15 March 2019, the US Food and Drug Administration (FDA) released an updated letter to healthcare providers detailing that while the results of their preliminary review of the JAHA meta-analysis

September 2019 | Issue 75 data was ongoing, they had “identified a potentially concerning signal of increased long-term mortality in study subjects treated with paclitaxel-coated products compared to patients treated with uncoated devices”.

The statement also noted that each of the trials used “all-cause” mortality calculation methods that differed significantly and had the potential to influence the way those results were interpreted.

The three pivotal premarket trials evaluating paclitaxelcoated products for the treatment of peripheral artery occlusive disease that informed this statement— Medtronic IN.PACT SFA I and II; Cook Zilver PTX; and BD LEVANT 2 randomised controlled trials—each used a different methodology to calculate mortality. “To facilitate a direct mortality comparison between the three trials”, Holden and colleagues write that they “asked each of the companies to provide five-year mortality using the same proportional methods as used by Medtronic [calculated as the number of patients who died divided by the number of patients followed up to five years]”.

Explaining the rationale behind this strategy, Holden et al say: “This consistent methodology allowed for a direct comparison of product dose to test the dose-response theory proposed by the meta-analysis. The highest fiveyear mortality was found to be associated with the lowest paclitaxel dose device (Zilver PTX), while the lowest mortality was associated with the highest dose device (IN. PACT). It is our view that this directly refutes the causal relationship theory between paclitaxel dose and all-cause mortality.”

Using this proportional method, the investigators report no significant difference in the five-year mortality between paclitaxel-coated balloons compared to controls in the Medtronic IN.PACT and BD LEVANT 2 trials.

The Zilver PTX DES displayed a significant difference (p=0.008) between the arms. When the Zilver PTX randomised controlled trial five-year data are reanalysed by an intention-to-treat analysis, the mortality of the paclitaxel-eluting stent remains the highest (22.7%) of the

three devices, but the mortality difference compared to the control arm (18.5%) loses its significance (p=0.45).

As patients previously lost to follow-up are contacted and potentially added into the analysis, the proportional calculation may differ (as the denominator, number of patients follow-up to five years, will increase), though the study authors do not think this will change the outcome.

Commenting on these findings, Holden and colleagues say: “We believe it is likely, even with more complete patient follow-up, that the lack of correlation between paclitaxel dose and mortality will persist”. They suggest Kaplan Meier survival plots could be calculated in the future, if more data were collated.

As Holden et al believe the causation theory behind paclitaxel and mortality “now appears unlikely”, they suggest several alternative hypotheses to explain the JAHA meta-analysis results, including performance and detection bias, trials being inadequately powered for mortality, significant target lesion crossover from the control to treatment arms, and patients lost to follow-up.

They conclude: “Perhaps the most important lesson from this paclitaxel debate may be the need to reconsider and significantly modify the way vascular device trials are performed in the future. We believe there should be an additional emphasis placed on adherence to guidelinesbased medical therapy of all enrolled patients as well as safety endpoints such as mortality. Greater effort must be made to reduce subjects lost to follow-up and properly classify the mortality status of those subjects who withdraw.

“It is only with well-conducted safety evaluations that we will completely clarify this issue regarding paclitaxel.

Given the known and undisputed benefits of paclitaxel coating on stents and angioplasty balloons, we owe it to our patients to pursue that truth before we restrict these devices from use.”

The medical community awaits an individual patient data meta-analysis to provide greater clarity regarding the alleged link between paclitaxel and mortality.

Vascular access

Issue 75 | September 2019

“More creative solutions” needed for end-stage vascular access patients Nick Inston Comment & Analysis Nick Inston calls for “more creative solutions” to vascular access challenges, commending interventional radiologists’ innovative reputation as instrumental to increasing the number of treatment approaches available to physicians. Outlining the complexities of end-stage vascular access in an ever-increasing patient population, Inston expresses the need for a multidisciplinary team approach, claiming that the “outlook is improving” due to the fruitful crosspollination of ideas and skills.

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he age of the dialysis population continues to increase, and whilst some of this may be attributed to older patients initiating dialysis, the main component is improved survival in prevalent dialysis patients.

As a consequence, the vascular access needs of this population become more challenging. As primary access sites become depleted, more creative solutions must be employed.

In a small but increasing group of patients, standard, multiple, autologous, and synthetic options may have all failed, and these patients may be deemed to have exhausted all vascular access options except for the use of a central venous catheter (CVC). This situation may be termed end-stage vascular access (ESVA).

If a patient with a limited lifespan expresses a wish to remain on a CVC, this may be a suitable option.

However, this group of patients are likely to require multiple interventions to maintain their CVC patency and may require kinase infusions and even emergency CVC exchange to maintain an ability to dialyse.

In those patients keen to pursue definitive access options, classifying the underlying issues is helpful.

This can be done on an anatomical basis such as the radiological classification outlined by the Society of Interventional Radiology, or by using a simplified, more basic classification, such as that described by Julien Al-Shakarchi (University Hospital Birmingham, Birmingham, UK).

A simple classification for endstage vascular access failure is proposed based on a sequential broad categorisation of: stage 1) no upper limb vascular access option; stage 2) no lower limb vascular access options; stage 3) no vascular access options at any site.

These can have the underlying anatomical problem added to allow more detailed definition (see Table 1).

An illustrative example may be a patient with tight superior vena cava (SVC) and brachiocephalic stenosis who has a right iliac vein occlusion and a left groin line. This would be classed as ESVA 2a, and possible solutions that could be considered are a left femoral vein transposition or loop thigh arteriovenous (AV) graft, attempts at recanalising the upper body central veins with recanalisation and stenting, or use of a Surfacer device (Bluegrass Vascular) and insertion of a HeRO (Merit Medical).Other options may be a non-standard graft configuration—here a right axillo-femoral graft may be possible. Peritoneal dialysis should not be forgotten.

When balancing each of these the

risks and benefits should be carefully considered.

Lower leg access is not without complications. Femoral vein transposition, whilst having the advantage of use of the autologous vein and of reducing infection, is associated with lower limb congestion and venous insufficiency. Additionally, amputation has been reported with this method.

Lower limb prosthetic grafts are associated with high rates of infection and low patency.

Recanalisation of upper body central vessels may require expert interventional radiology skills and devices. The Surfacer device has potential, but robust data are not yet available to allow evaluation. Even with recanalised vessels the next step towards definitive access requires either extensive stenting or the use of a HeRO device. In patients with CVC infections (common in groin access), this is contraindicated. In such patients, a staged approach to recanalisation with initial upper body CVC, eradication of infection, and subsequent conversion to a HeRO graft may be a better approach.

Patients with arterial insufficiency can pose a problem and inadequate inflow may not only threaten the access, but also the limb. The resistance within longer grafts and HeRO grafts requires a suitable inflow including a reasonable blood pressure. Hypotension should be carefully evaluated when these options are being considered.

A further consideration is that of transplantation. Younger patients with ESVA may have had a long history of renal replacement and multiple CVCs. In the example above, a groin line in the only patent iliac vein poses a great threat to future kidney transplantation.

It may be proposed that such patients are considered higher priority in organ

Stage ESVA

Potential options for definitive vascular access

1. No upper limb VA option a. A xillary vein stenosis a. S ubclavian vein stenosis b. B rachiocephalic/ innominate vein stenosis c. SVC stenosis

- Non-standard graft configurations (e.g. necklace) - Sharp recanalization and HeRO - Surfacer + HeRO - Lower limb options

2. No upper limb VA option a . Iliac stenosis b. I VC stenosis

- Contralateral femoral vein transposition or AVG - Non-standard graft configurations - Sharp recanalization and HeRO

- Arterial arterial prosthetic loop 3. No options at -A xillary right atrial graft any site c. C VC via a nonstandard site (e.g. translumbar, transhepatic, other) d. N o access options and treatment withdrawal Table 1. Stages of ESVA from Al-Shakarchi et al. The classification has arterial insufficiency (including hypotension) which has been removed from this table as different approaches are required

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allocation schemes as a working transplant is their optimal option. When considering such patients for lower limb access there is little to support avoidance of lower limb options and many transplants have been performed successfully above patent ipsilateral loop thigh grafts.

For patients where attempts to gain access are unsuccessful—stage 3 ESVA—there are still solutions that can be found.

This group traditionally were treated with a translumbar or transhepatic CVC. For many this was seen as a pre-terminal option, although data support reasonable short and mid-term survival.A relatively simple definitive option in these patients is the arterial arterial prosthetic loop (AAPL), which is an interposition graft in the subclavian/axillary artery.

This unique configuration requires special consideration when cannulated and cannot be used for drug delivery but has been shown to have good patency with low complications.

Smaller series of axillary atrial grafts are published and advocated by some authors, however complications are greater and more significant.

In deciding treatment options, an access life plan should be defined, as highlighted in the recent Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines from the National Kidney Foundation. Where multiple options exist, these should be considered and staged with the simplest and safest option first, whilst retaining the possibility of further interventions later down the line.

The best approach to managing these difficult cases is with a multidisciplinary team, using a treatment utilising their experience and expertise, and chosen based on its applicability to the patient. The availability of surgical and radiological expertise is required not only for the index procedure, but also for many of these patients’ subsequent interventions and salvage procedures, conducted to maintain patency. An identified pathway should be defined with access to suitable facilities to allow this.

ESVA provides a very challenging problem for the vascular access surgeon, and the bad news is the incidence is likely to increase.

Fortunately, there are an increasing number of possibilities for treatment with innovative devices and techniques.

Historically, the prognosis was bleak for patients with ESVA, but by combining surgery and interventional radiology skills, the outlook is improving. As always in access, the approach used should be the right access, for the right patient, at the right time. This applies especially to ESVA, where the whole team’s input and detailed discussion with the patient are essential.

Nick Inston is a consultant transplant and vascular access surgeon at the University Hospital Birmingham NHS Trust, Birmingham, UK.

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Paclitaxel devices

September 2019 | Issue 75

Interim safety analysis of PAVE trial data identifies “no concerns” regarding mortality and paclitaxel devices in AV access Providing an update on the UK-run PAVE trial (paclitaxel-assisted balloon angioplasty venous stenosis in haemodialysis access) at the 2019 EndoVascular Access Meeting (EVA; 21–22 June, Patras, Greece), Narayan Karunanithy (Guy’s and St Thomas’ Hospital and King’s College London, London, UK) explained that although recruitment had slowed to six months behind schedule, the one-year results will be released in autumn this year.

THE PAVE TRIAL was established in would like to say”, Karunanithy declared 2016 to assess the efficacy of paclitaxelat EVA, “is that we have identified no coated balloon angioplasty in addition to concerns with regards to morbidity or high-pressure balloon angioplasty to treat mortality [when using paclitaxel-coated dysfunctional native haemodialysis access. balloons], but there will be more detailed The double-blind, multicentre, randomised information about this that will come out controlled trial is funded by the National following our baseline data lock”.

Institute for Health Research (NIHR).

The investigators are currently Karunanithy explained at EVA that, “given performing this baseline data lock, which recent developments”, the triallists hope to Karunanithy describes as “quite a rigorous extend follow-up to five years. process […] looking at data management Narayan Karunanithy This comment is in response to and data verification of a huge number of the publication of a meta-analysis in case report forms”. He explained: “We have December 2018 by Konstantinos Katsanos (Patras, got a very rigorous continuous programme of in-house Greece) et al, who, writing in the Journal of the endpoint checking for fistulograms done at the time of American Heart Association (JAHA), reported an intervention or follow-up. In addition, we have a robust increased risk of death at two and five years following independent core lab analysis programme that is ongoing the use of paclitaxel-coated balloons and stents in the for patients treated in this trial.” femoropopliteal artery.

The PAVE trial completed its enrolment of 212 patients In the last three months, Karunanithy and colleagues on 4 October 2018, following an extension to the study have conducted an interim safety analysis with the timeline approved in July that year. The patients are patients enrolled in the trial so far. “The statement we randomised 1:1, to either the treatment arm (angioplasty

Interim results of a multicentre analysis support paclitaxelcoated balloon use in CVS The interim results of a multicentre, European, retrospective analysis investigating the use of drug-coated balloons (DCBs) in symptomatic central venous stenosis (CVS) suggest that these devices could be a valid option for treatment, slowing down the effect of neo-intimal hyperplasia (NIH) leading to restenosis. Though with data mining still underway, the investigators warn against drawing any premature conclusions. Panagiotis Kitrou (Patras University Hospital, Patras, Greece) presented these preliminary results at the annual EndoVascular Access Meeting (EVA; 21–22 June, Patras, Greece) earlier this year.

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gainst the backdrop of the current paclitaxel controversy (where Konstantinos Katsanos, along with Kitrou and other colleagues, reported in the Journal of the American Heart Association (JAHA) an increased risk of death at two and five years following the use of paclitaxel devices), Kitrou first provided insight into how the publication has affected his own clinical practice. He told delegates: “We [at Patras University Hospital] have not changed our practice with regard to DCB use in dialysis access management.

We believe that paclitaxel is an independent predictor of death, but its effect is different in different populations. Thus, a claudicant suffering more comorbidities compared to a claudicant with fewer comorbidities will have a greater number of factors antagonistic for the same event, which is

death. Hence the signal and the effect of paclitaxel becomes faint and diluted while the actual benefit from NIH inhibition becomes more apparent.”

For patients with CVS, the gold standard treatment is percutaneous transluminal angioplasty (PTA).

“However”, Kitrou explained, “the patency rates may be as low as 28.9% at six months. This rate doubles to 60% when you use a high pressure balloon.

The main problem [when using balloons] remains elastic recoil. You may also use a stent or a covered stent, with the latter being a much more aggressive treatment”.

Going through today’s evidence on CVS treatment, Kitrou showed EVA attendees the results from a 2015 retrospective analysis by Alexander Massmann et al that compared standard balloon angioplasty

with a paclitaxel-coated balloon) or to the control arm.

The primary endpoint is time to end of clinically-driven target lesions primary patency. The investigators have a number of secondary endpoints, looking at radiological, clinical and nephrological outcomes such as target lesion late lumen loss, procedural success, and the number of thrombotic events, as well as the number and severity of adverse events and patient quality of life assessment.

When listing the inclusion and exclusion criteria for the study, Karunanithy drew the EVA audience’s attention to the fact that only patients with a single lesion were investigated. He said the rationale for this was “to keep the data as clean as possible”, though later admitted that this was the primary reason why consented patients were later rejected from inclusion in the trial analysis. Of 482 consented patients, only 212 were randomised to one of the study arms, giving an eligibility rating of 44%.

However, when talking of patient follow-up, Karunanithy is content, saying: “We have got a very tight follow-up, so we are very happy with our follow-up regime for these patients—out to 24 months for some of the earlier recruited patients”.

The triallists have also been monitoring, in a blinded fashion, the event rate for their patient cohort. Without knowing which side of the study the patients are on—the treatment arm or the placebo arm—the investigators report that the event rate appears to be on target to meet their primary and secondary endpoints. To date, 45 of 211 patients (21.3%) have lost target lesion primary patency, and 46 of 211 patients (21.8%) have lost access circuit primary patency.

We have identified no concerns with regards to morbidity or mortality.”

with paclitaxel-coated balloon angioplasty for symptomatic central vein restenosis in patients with impaired native haemodialysis fistulas. The study investigators concluded that paclitaxel-coated balloon angioplasty yielded a statistically significant longer freedom from target lesion revascularisation compared to standard balloon angioplasty.

Although, Kitrou noted, Massmann and colleagues did include axillary veins, so he thinks these results “are not strictly for central veins”.

He next talked the audience through his own randomised controlled trial from 2017, which included 40 patients with de novo, restenotic and occluded lesions.

Twenty patients were treated with the Lutonix DCB (BD), and twenty were

We believe paclitaxel is an independent predictor of death.” treated with a non-coated balloon. In this study, the primary endpoint was a clinically-assessed intervention-free period.

In this, Kitrou et al found a significant difference in favour of DCBs. Additionally, DCB angioplasty was numerically better in the longitudinal analysis compared to plain balloon angioplasty.

Despite the fact that these studies found a significant difference between treatment arms consistently in favour of paclitaxel-

coated balloons, Kitrou highlighted that these results have been observed in fewer than 30 patients. The present multicentre, European retrospective analysis therefore will provide data detailing DCB use in a greater number of patients. The primary outcome measures are a clinicallyassessed intervention-free period of the treated segment at six months, a dialysis access circuit with no need for clinically driven target lesion repeat intervention for symptom recurrence (verified angiographically), and no procedurerelated minor and major complications.

The study included 87 patients from 11 centres across Greece, Germany, France, Italy, Portugal, and the UK. Though still only early data, the interim analysis reveals that at six months, the target lesion primary patency was 52%, and the median target lesion primary patency was 280 days, meaning lesions remained open following intervention for an average of nine months. “The results are already much better compared with our randomised controlled trial”, Kitrou said, referring to his 2017 study.

The investigators also measured primary patency of the access circuit. This was 48% at six months, and the median time to reintervention was 257 days. The access circuit survival was approximately 70% at six months, Kitrou shared.

“There is a lot of work in progress, we are still mining data—we are looking at this huge Excel [document] with a lot of data in there, and we will soon have more to share with you”, Kitrou concluded.

AV grafts

Issue 75 | September 2019

No significant differences between hybrid and open approaches for managing thrombosed AV grafts Data from the University of Pittsburgh Medical Center (Pittsburgh, USA) indicate that the open approach to managing thrombosed haemodialysis grafts with venous anastomotic lesions is not associated with superior primary patency when compared to the hybrid approach. These findings also show that an existing stent in an arteriovenous graft (AVG) is a strong predictor of loss of patency and graft abandonment.

Catherine Go

atherine Go (Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA) presented the data at the 2019 Society for Vascular Surgery (SVS) Vascular Annual Meeting (VAM; 12–15 June, National Harbor, USA). She told delegates that AVG were “plagued by poor patency” and failure of an AVG leads to “increased cost and morbidity”, adding that thrombosis in an AVG most commonly occurred because of a venous anastomosis stenosis.

However, according to Go, the “jury is still out” about how to manage such thromboses. Two meta-analyses— published in 2002 and 2019—have reported the superiority of the open treatment over purely endovascular methods, but few studies have

thrombectomy to first reintervention or thrombosis) and secondary patency (time from index thrombectomy to graft abandonment). The investigators also reviewed technical success and primaryassisted patency (time from index thrombectomy to first rethrombosis).

Overall, 97 patients underwent intervention for occluded AVGs at the University of Pittsburgh Medical Center between 2014 and 2018. Of these, 34 underwent the open approach (73.5% patch angioplasty and 26.5% jump bypass) and 63 (22.2% stent graft, 7.9% cutting balloon, and 1.6% bare metal stent) underwent the hybrid approach.

At 30 days, there were no significant differences in rate of the failure of the approach: 29.4% for open vs. 27% for hybrid (p=0.799). A multivariate

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investigated the hybrid technique, which Go reported is commonly used at her centre (University of Pittsburgh Medical Center). She explained that this involves “open thrombectomy followed by endoluminal treatment (balloon angioplasty, cutting balloons, or stents/ stent grafts)”.

“Based on historical data, we hypothesised that open revision for AVG venous anastomosis is associated with better patency when compared to hybrid therapies”, Go stated. Therefore, in the retrospective study, Go and colleagues compared patency outcomes for patients who underwent open repair for a first-time AVG thrombosis with those for patients who underwent the hybrid approach. The primary endpoints were primary patency (time from index

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analysis showed that a higher number of prior fistulograms and African-American race were both predictive of protection against failure. There were also no significant differences between groups in primary patency, primary-assisted patency, or secondary patency at either six months or 12 months.

Go reported that the number of prior fistulograms was again predictive of protection against primary patency failure (at six/12 months). Central occlusion and a hypercoagulable state were predictive of loss of primaryassisted patency. An existing venous anastomosis stent predicted both loss of primary patency and loss of secondary patency.

“AVG patency after thrombectomy is poor. Open versus hybrid treatment of AVG venous anastomosis stenosis are not associated with differences in patency. An existing stent at the venous anastomosis is a strong predictor of loss of patency and abandonment,” Go reported. She added that, given the association between an existing stent and graft abandonment, an operator should “start planning future access options” when using a stent to salvage a thrombosed AVG.

Arteriovenous graft patency after thrombectomy is poor.”

Critical limb-threatening ischaemia

Issue 75 | September 2019

Global vascular guidelines on chronic limb-threatening ischaemia: Redefining a critical disease The publication of the global vascular guidelines on the management of chronic limb-threatening ischaemia this year sees the product of four years of collaborative work by vascular experts and societies around the world. The goal of having surgeons and providers to agree on the optimal treatment pathways for patients with chronic limb-threatening ischaemia was described in an announcement from the Society for Vascular Surgery as a “quixotic quest”, which had come to fruition in the guidelines’ publication.

The document was published in two of the societies’ journals: the European Journal of Vascular and Endovascular Surgery (EJVES) and the Journal of Vascular Surgery (JVS).

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roduced in a joint effort by the European Society for Vascular Surgery (ESVS), Society for Vascular Surgery (SVS) and the World Federation of Vascular Societies (WFVS), the document focuses on the definition, evaluation and management of a large world-wide patient population and a disease associated with mortality, amputation, and impaired quality of life.

With particular emphasis on guiding evidence-based practice, creating standardised frameworks for treatment as well as research, providing insight into areas of low-level evidence or unmet needs and changing the overall perception of the disease to include a wider spectrum and stages of severity.

Co-editors were Michael Conte from the Society for Vascular Surgery, Philippe Kohl from the European Society for Vascular Surgery and Andrew Bradbury from the World Federation of Vascular Societies. Nearly 60 additional authors worked on the project. Participants spanned six continents and represented all specialties that treat chronic limbthreatening ischaemia.

In the effort to create a set of collaborative joint guidelines, Conte told Interventional News prior to their publication: “The very first and most important project that we undertook was advanced limb ischaemia—which we are now calling chronic limb-threatening ischaemia.”

From CLI to CLTI: What is in a name?

The shift in terminology from the widely used definition of critical limb ischaemia (CLI) to chronic limb-threatening ischaemia (CLTI) is indication of a key shift in conceptualising, identifying and treating this patient population. “We have changed the terminology around this problem”, Conte said, “to recognise the fact that in current practice, what constitutes limb-threatening ischaemia may be different in different scenarios. The previous concept of critical limb ischaemia suggests that there is some threshold value of perfusion below which everyone is critical, and above which everyone is okay.

What we realised is that with diabetes and the expanding range of neuroischaemia that we see in patients, more moderate ischaemia may still be limb-threatening in certain situations when there are large wounds and bad infections. In current vascular practice, we are treating more of those patients, so I think in current times to pretend that there is a critical measurement that we can say defines ‘critical’, is really not reality. Instead, we prefer the name ‘chronic’, to denote something that is present for at least two weeks. ‘Chronic limb-threatening ischaemia’ describes the whole spectrum of wounds, ischaemia and foot infection.”

revascularisation in CLTI is linked to both the severity of ischaemia and the degree of limb threat, the guidelines state.

The guidelines further highlight that CLTI is associated with advanced age, multiple comorbidities, and frailty.

Therefore, while goals of treatment include relief of pain, healing of wounds, and preservation of a functional limb, the authors note that revascularisation “may incur significant morbidity and mortality, requiring multiple hospitalisations, prolonged outpatient care, and thus considerable health and social care costs.

Whereas the majority of patients with CLTI should be considered candidates for limb salvage, some may be appropriately treated with primary amputation or palliation after shared decision-making.”

“Once you know how severely threatened the limb is,” Conte explained to Interventional News, “the next stage in whether the patient is a candidate for revascularisation is to look at vascular anatomy.” The extent of benefit of revascularisation, the guidelines state, is also linked to anatomic durability of the selected intervention, adding: “these concepts are central to PLAN and to the development of evidence-based revascularisation strategies in CLTI.” Although the anatomic pattern of arterial occlusive disease is described as a “dominant consideration” in evidencebased revascularisation, it is importantly set out in PLAN as clearly secondary to “the broader context” of patient risk and limb threat. Using the classification and staging systems proposed in the guidelines to define the pattern and severity of limb disease, specialists can better identify the

Once you know how severely threatened the limb is, the next stage in whether the patient is a candidate for revascularisation is to look at vascular anatomy.”

Optimising decision-making with a PLAN

Patient risk estimation, limb staging and anatomic pattern of disease is the focus of a decision-making process with the acronym PLAN, set out by the authors of the guidelines and described by Conte as “a new framework of decision-making that starts with the patient, then looks at staging the limb—and only then looks at staging the vascular anatomy”. This method emphasises a structured approach in decision-making, which according to Conte “is very important because over the last number of years, with the evolution of technology, there has been an overemphasis on vascular lesions, to the detriment of not thinking about the patient and the limb first.”

Instead, the first stage of the PLAN approach is to assess the risk of the patient, both the peri-operative risk and the long-term survival, as well as ambulatory function and goals for treatment. The second step is limb staging, determining whether the limb is salvageable and defining the severity of the disease. The presumed benefit of

optimal strategy for intervention with the knowledge that the intervention is also the right step for the patient at this stage.

The endorsed system for accurately staging the severity of limb threat is the SVS’ threatened limb classification based on grading of wounds, ischaemia and foot infection (WIfI). The WIfI system is widely used already, but is complemented in the PLAN strategy by a new system created for these guidelines: the Global Anatomic Staging System (GLASS).

“In the new guideline,” Conte explained to Interventional News, “we are proposing a new way to stage the vascular anatomy that really is more in line with the way we think in CLTI, which is ‘how do we restore inline flow from the groin all the way to the foot’—not one lesion at a time, but to get it all the way there. Often in these patients, that means crossing more than one lesion, because most of them have multi-segment disease. The outcomes are a multiplier of each other; they are not one at a time.”

GLASS introduces two novel concepts: firstly, the so-called target

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arterial path and secondly, an estimated limb-based patency.

Limb-based patency, the guidelines clarify, is defined as maintenance of in-line flow throughout the target arterial path, from groin to ankle. This allows for a “more direct comparison of anatomic outcomes across revascularisation strategies in CLTI”, the authors state, as the “complexity of disease traversed by the target arterial path is integrated in the GLASS”.

“When you have an angiogram, the surgeon or interventionalist decides which is the below-the-knee target that they are trying to get open all the way to the foot,” Conte expanded. “Then, you take a line and draw from the groin, through the target artery to the foot so that you can define a complexity of that pathway based on the location, length and severity of stenoses or occlusions which, by consensus, we then grouped in to three categories.”

The GLASS stages I to III correlate with low-, intermediate-, or highcomplexity infrainguinal disease patterns, the authors state in the guidelines document. There is also an expected correlation to immediate technical success and one-year limb-based patency for endovascular intervention. However, as a novel system created for this purpose, there is not yet any prospective data to validate the tool. On the potential limitations of the guidelines, Conte commented that he expects some criticism levelled against the introduction of the endorsed staging systems, due to the lack of prospective validation.

However, he points out, “Neither was TASC when it first came out; neither were many cancer systems when they first came out. People sit down and think about the problem, and they think about what makes sense in terms of how to group it, and then when we get more data, the staging system should be modified to reflect prospective data.”

Another potential limitation identified by Conte is in the strength of recommendations in areas where evidence is lacking. “There was always disagreement about the strength of evidence that might support some of the previous guidelines,” he told Interventional News. “Should the guidelines follow practice, or should the guidelines follow evidence—and should evidence guide practice? Those are two very different things, because marketing drives practice sometimes.”

Conte describes only a “small fraction” of recommendations in the guidelines as “high-level grading in terms of strength and evidence”, while “many others” are weaker, and some are simply “just goodpractice statements”.

“Finally,” Conte added, “there are a couple of areas that the guidelines will show where we literally have just said it is indeterminate for this type of patient which approach might be best, and frankly there is no consensus in some of these cases.”

By highlighting such areas, the authors hope that funding agencies and industry will be able to better help fill in those gaps in knowledge in the future.

Catheters

Issue 75 | September 2019 ADVERTORIAL SPONSORED BY GUERBET

SeQure® microcatheter: A new kid on the block for a better controlled embolization reduces the risk of nontarget embolization Geert Maleux discusses the challenge presented by trying to avoid nontarget embolization when performing catheter-directed embolotherapy. As an all too common complication, Maleux argues that the SeQure® microcatheter (Guerbet) appears to be a promising solution to evade the backflow of microparticles whilst still conducting the embolization in “free flow”.

NONTARGET EMBOLIZATION remains one of the most common complications related to catheterdirected embolotherapy. Various causes of nontarget embolization have been identified, including backflow of embolics into nontarget arteries, poor catheter tip positioning proximal to nontarget vessels, or embolization of a target vessel associated with an arteriovenous fistula.

Nontarget embolization is well-known in hepatic (chemo-)embolization, but may also occur in other territories, including bronchial, gastrointestinal, uterine or prostate arteries. Potential complications

related to nontarget embolization might be asymptomatic, but in a substantial number of cases, these complications can result in serious clinical symptoms prompting immediate treatment. Type and severity of complications depend on several factors, including the vascular territory embolized, the type and amount of embolics used, and the general status of the patient.

In hepatic (chemo-)embolization, nontarget embolization of hepatoenteric vessels may result in ischaemic cholecystitis, pancreatitis and gastritis, or even in gastroduodenal ulceration.

Nontarget embolization following

Fig. 1: dual-phase cone-beam CT before chemoembolization reveals predominant right-sided colorectal liver metastases (arrow) with central necrosis.

bronchial artery embolization may result in muscular pain, dysphagia, or even paraplegia if embolics are unintentially injected into the intercotal, Geert Maleux aesophageal, or spinal arteries, respectively.

In the pelvic region, nontarget embolization may occur during prostate artery and uterine artery embolization.

In case the rectal or vesical artery is embolized during prostate artery embolization for the treatment of benign prostatic hypertrophy, this may result in lower gastrointestinal or bladder ulceration, respectively. In uterine artery embolization for the treatment of myoma, nontarget embolization is clinically less frequent, but reports dealing with vaginal mucosa or skin ulceration have been described.

In clinical practice, a substantial number of inadvertent complications related to nontarget embolization can be avoided by careful analysis of the angiographic images obtained during the embolization procedure and by slow injection of the embolics under fluoroscopic guidance. However, even in experienced hands using the best angiographic equipment, nontarget embolization is still a problem. It is not surprising that many researchers have tested various interventional techniques to avoid complications of nontarget embolization: protective proximal

coil-embolization of nontarget vessels, like coil- or plug-embolization of the proximal right gastric or gastroduodenal artery prior to hepatic chemo- or radioembolization; use of an occlusive balloon to avoid backflow or to perform subtotal embolization in case the target artery can only be cannulated proximal to nontarget vessels.

In order to avoid backflow of microspheres during embolotherapy and still perform the embolization procedure in ‘free flow’, the SeQure® microcatheter seems to be a promising solution. In vitro and animal studies have already shown the efficacy in reducing backflow of microspheres during embolization in various arterial territories, compared to regular microcatheters with use of the same type of microspheres (diameter >70 microns). Additionally, use of the SeQure® microcatheter also resulted in the delivery of a higher amount of microspheres into the target tissues, whitch could result in better clinical outcomes, for example in chemoembolization, bronchial artery embolization, or even in uterine or prostate artery embolization. However, multicentre, comparative studies are needed before implementing this new technology as the standard of care for these embolization procedures.

Fig. 2: selective hepatic angiography before DEBIRI-chemoembolization reveals homogeneous opacification of the right and left liver lobe.

Fig. 3: selective hepatic angiography after DEBIRI-chemoembolization with use of the Sequre microcatheter shows postostial occlusion of the right hepatic artery (arrow) and fully patent left hepatic artery (arrowheads) and end branches.

“Unprecedented” development of NICE aortic aneurysm guideline The draft version of the National Institute for Health and Care Excellence (NICE) guideline created a furore, when released for consultation in 2018, with its recommendation that patients with an unruptured aneurysm should only be offered open surgery, if they were fit and able to undergo the procedure. Many stakeholders have called the draft guideline “unimplementable” and its publication has been repeatedly deferred since then.

“THE GUIDELINES NOW sits with the NICE Board,”

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says Ian Loftus (London, UK), president of the Vascular

Geert Maleux, MD, PhD, is an interventional radiologist in the Department of Radiology, University Hospitals KU Leuven, Leuven, Belgium.

He has received consulting and speaker honorary from Guerbet.

Society for Great Britain and Ireland (VSGBI), who calls this step unprecedented.

“There must be compromise on both sides and re-wording to make this guidance workable,” he tells Interventional News, noting that NICE is working closely with the stakeholders to progress the guideline.

VSGBI and the British Society of Interventional Radiology (BSIR) have together been in discussion with NICE and communicated the concerns of the vascular community. In a letter to members of VSGBI, Loftus writes: “It has been challenging for all concerned and at present there is no date set for publication. We remain in touch with NICE, [...] and have reiterated our desire to help to find a workable solution that is in the best interests of our patients.” VSGBI raised concerns about the wording of the guidelines with both NICE and BSIR, but were unable to change it.

MedTech Insights

Issue 75 | September 2019

UK consensus statement on renal denervation “strongly encourages” clinicians to tell patients about ongoing trials In a new consensus statement, the Joint UK Societies (JUKS)— which includes the British Society of Interventional Radiology— say that the evidence for renal denervation is “insufficient” to recommend its routine use in clinical practice. However, they add that they support ongoing clinical trial programmes of renal denervation and “strongly encourage” clinicians to tell their hypertensive patients about such studies.

MELVIN D LOBO (William Harvey Research Institute, Queen Mary University London, London, UK) and colleagues write in Heart that a previous JUKS consensus statement on renal denervation—published in 2014—“placed a moratorium” on the use of renal denervation in routine UK clinical practice until further “favourable evidence had emerged”.

They explain that the 2014 statement was in response to the results of the SYMPLICITY HTN-3 trial, which found that renal denervation with the Symplicity system (Medtronic) did not significantly reduce blood pressure compared with a sham procedure.

According to Lobo et al, recommendations from this 2014 statement and those from the European Clinical Consensus Conferences “led to new and improved clinical trials of renal denervation utilising input from experts in the field to lead on both the design and execution of studies in collaboration with commercial sponsors”. Therefore, now that several of these studies have been published, JUKS have published a new consensus statement to “consider the new evidence that they provide”.

The authors review data both for Medtronic’s radiofrequency Symplicity Spyral system and for ReCor Medical’s ultrasound Paradise system, noting that both systems have been associated with significant reductions in ambulatory blood pressure (albeit in different

patient populations).

“The SPYRAL and RADIANCE [Paradise] study programmes to date have provided encouraging data to suggest that renal denervation may have a role Melvin D Lobo in the treatment of hypertension,” Lobo et al comment.

They add that, together, the studies have shown the “value of collaboration” better different disciplines (including industry) and “rekindled enthusiasm for renal denervation in the clinical community”.

However, Lobo et al outline the limitations of the studies—such as being of short duration—and that the studies have “reported considerable heterogeneity in the response to renal denervation”. Furthermore, they note: “At present, it is unclear which technology may be best for renal denervation, with radiofrequency and ultrasound systems appearing more or less similar in efficacy, and ongoing trials of chemical ablation systems are not published yet.”

Thus, Lobo et al report that the JUKS are not changing their position that there is “insufficient evidence to recommend the routine use of renal denervation and that the use of renal denervation should remain restricted to clinical trials”.

They do though provide an “agenda” for important areas for future research.

These areas include further studies to determine the role of renal denervation in the treatment of hypertension, establishing the safety/durability of different renal denervation technologies, and identifying which patients will be the best responders.

Although they do not advocate the use of renal denervation in routine clinical practice, Lobo et al say that the JUKS support ongoing clinical trial programmes from the different device manufacturers across the spectrum of renal denervation technologies. They add that they “strongly encourage clinicians who look after patients with hypertension to inform their patients about these studies, which are recruiting participants who are on and off medications in order to inform future practice.”

Lobo told BIBA Briefings that he thinks there will be a definitive answer about the role of renal denervation for managing hypertension in “the next two to three years”.

Expanding the role of renal denervation

The need for further studies to better understand the role of renal denervation to manage hypertension has not, however, prevented studies exploring the use of the procedure to treat other cardiac conditions. Lobo said: “I think these studies make a lot of sense particularly where those conditions are characterised by high sympathetic drive. The design of these studies, however, will need

I think these studies make a lot of sense, particularly where those conditions are characterised by high sympathetic drive.” to be very carefully thought out given how complex it has been to evaluate the efficacy of renal denervation for hypertension.”

Speaking at EuroPCR 2019 (21–24 May, Paris, France), Marshall Heradien (Department of Internal Medicine, Stellenbosch University, Tygerberg, South Africa) presented a study that evaluated the use of renal denervation for the management of atrial fibrillation. He said that several previous studies “support the idea that renal denervation may have an antiarrhythmic effect”, adding that he and his fellow investigators sought to test the hypothesis that “upstream renal denervation treatment can reduce atrial fibrillation in patients with hypertensive heart disease”.

In the study, 42 patients were randomised to receive treatment with renal denervation (10 with the firstgeneration Flex catheter and 32 with the

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second-generation Spyral catheter and 38 underwent “sham” renal denervation. The primary endpoint was the first event of subclinical atrial fibrillation of at least six minutes on an implantable loop recorder (which was scanned at six-month intervals).

After an average of three years of follow-up, 19% of the renal denervation group had an episode of atrial fibrillation compared with 47% of the sham procedure group (0.011). Furthermore, patients in the sham procedure experienced significantly more episodes of fast atrial fibrillation: 12% vs. 2% (p=0.002). Renal denervation was also associated with a significant reduction in cardiovascular death at two years: one patient versus six patients for the sham procedure (p=0.04). However, there were no significant differences in office systolic blood pressure at six months between groups.

Heradien concluded: “In this single-centre randomised controlled trial of patients with hypertensive heart disease, upstream treatment of renal denervation reduced subclinical and fast atrial fibrillation and cardiovascular death.”

Renal denervation has also been explored for the management of heart failure secondary to Chagas’ disease. In Catheterization and Cardiovascular Interventions, André G Spadaro (Heart Institute, University of São Paulo Medical School, São Paulo, Brazil) and others report that renal denervation was “safe and feasible” for patients with Chagas cardiomyopathy. They add that after nine months of follow-up, the primary endpoint (all-cause mortality, myocardial infarction, stroke, need for renal artery invasive treatment or worsening renal function) occurred in 36.4% of 11 patients randomised to undergo renal denervation, compared with 50% of six patients randomised to conservative treatment (p=0.06).

Spadaro et al state that these findings warrant “future studies to better evaluate the clinical efficacy of the interventional strategy in improving the prognosis of this high-risk population.”

BIBA Briefings BIBA Briefings is an online platform (www.bibamedtech. com/biba-briefings) that gives an in-depth analysis of the latest market intelligence from BIBA MedTech Insights (www. bibamedtech.com). It also reviews the latest technology news and pipeline developments.

For editorial enquiries, please contact Dawn Powell: dawn@bibamedical.com For sales enquiries (including BIBA MedTech Insights), please contact Merveille Anderson: merveille@bibamedical.com

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Interventional radiologists

September 2019 | Issue 75

Capping medical residency hours does not hamper new doctors’ quality of training When new rules capped training hours for medical residents at 80 hours per week in 2003, critics worried that the change would leave physicians-in-training unprepared for the challenges of independent practice. New research, published today in the British Medical Journal (BMJ) and led by scientists in the Department of Health Care Policy in the Blavatnik Institute at Harvard Medical School, shows that these warnings were largely unjustified.

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he analysis—believed to be the first national study examining the impact of reduced hours on physician performance—found no evidence that reduced training hours had any impact on the quality of care delivered by new physicians. This is notable given that recent polling from a recent survey sent out by physicians via SIR Connect (the Society of Interventional Radiology’s online discussion forum) found that there was a significantly increased risk of experiencing burnout, characterised by depersonalisation and emotional exhaustion, for those interventional radiologists who work more than 80 hours per week.

Following a series of high-profile patient injuries and deaths believed to stem from clinical errors caused by fatigue, medical accreditation agencies initiated a series of sweeping changes to the regulations governing resident

hours and other aspects of training. These efforts culminated in 2003 with the US Accreditation Council for Graduate Medical Education capping the training of medical residents at 80 hours per week.

“This is probably the most hotly debated topic in medical education among physicians,” says Anupam Jena, the HMS Ruth L Newhouse associate professor of Health Care Policy in the Blavatnik Institute, a physician in the department of medicine at Massachusetts General Hospital (Boston, USA), and lead author of the study. “Many doctors trained under the old system think that today’s residents do not get enough training under the new system. You hear a lot of senior physicians looking at younger doctors coming out of training and saying, ‘They are not as prepared as we were.’”

The findings of the study

New BSIR Women and Diversity committee aims to boost proportion of female IRs The British Society of Interventional Radiology (BSIR) established a Women and Diversity committee earlier this year, with the aim of overcoming obstacles to women and marginalised groups who are either already interventional radiologists or potentially will be in the future. The committee is discussing ways to encourage women to apply to the specialty, as well as how to make the work place as supportive as possible.

THE FIRST MEETING of the committee resulted in 12 proposals for action being made, which are currently being prioritised and implemented. These included a plan to develop social media forums (WIIGS@BSIR) led by Elika Kashef (London, UK), and a baseline survey with metrics to monitor the progress of the committee’s work over time led by Ros Ahmed (Leicester, UK). The group also intends to work with potential interventional radiology recruits from school age through to radiology trainees.

should assuage these fears, Jena believes.

The researchers found no significant differences in 30-day mortality, 30-day readmissions, or inpatient spending between physicians who completed their residency before and after the residency hour reforms.

“We found no evidence that the care provided by physicians who trained under the 80-hour-a-week model is suboptimal,” Jena comments.

Given the changes in hospital care over the past decade, the researchers knew that they could not just compare the difference between outcomes of recently trained doctors before and after the cap, since overall outcomes have improved thanks to better diagnoses and treatments, better coordination of care and new digital tools designed to prevent harmful drug interactions and other human errors.

Comparing new physicians trained before reform with those trained after would confound the effect of changes in training with the effect of overall changes in hospital care. To avoid conflating the two, the researchers compared new physicians before and after the reforms with senior physicians who had trained before the reform.

The study analysed 485,685 hospitalisations of Medicare patients before and after the reform. The training hour reforms were not associated with statistically significant differences in patient outcomes after the

In full, the 12 initial proposals are:

1. Develop Women and Diversity social media forums (for example using WhatsApp and Twitter) 2. Baseline survey of perceptions with metrics to monitor progress over time 3. Develop a BSIR area blog / newsletter / online forum 4. Work with Radiology trainees—encourage IR as an open specialty to all 5. BSIRT [British Society of Interventional Radiology Trainees] survey to identify barriers to entering interventional radiology 6. Attend / presence at meetings: Annual Scientific Meeting, Advanced Practice Course and Basics Course to access trainees.

7. Inspire future trainees early—attend A level fairs and medical student careers fairs 8. Support existing trainees—mentoring programme to include access / support for mentoring coaching 9. Provide a roadshow at careers fares / BSIRT meetings. With specific attention to barriers—flexible training and pregnancy 10. Promote leadership among interventional radiologists 11. Promote resilience / work–life balance / coaching 12. Produce a workshop for the Annual Scientific Meeting and IOUK [Interventional Oncology United Kingdom] Speaking of the importance of this work, committee member Shilpi Pal (Dundee, UK) says, “The presence of visible female role models was felt useful as a means to inspire future recruits. There was felt to be a need to encourage women into leadership roles, and to provide support once these roles have been taken on.” With this in mind the group is in the process of setting up a travelling grant. Tze Wah (Leeds, UK) adds: “It is a great honour that Professor Anna Maria Belli has agreed to allow us to name the grant after her”.

There is a national shortage of trained diagnostic and

physicians left training.

For example, 30-day mortality rates among patients cared for by first-year attending internists during 2000–2006 and 2007–2012 were 10.6% (12,567 out of 118,014) and 9.6% (13,521 out of 140,529), respectively. In comparison, the 30-day mortality among patients cared for by tenth-year attending physicians was 11.2% (11,018 of 98,811) and 10.6% (13,602 of 128,331) for the same years.

Further statistical analysis to eliminate the unwanted effects of other variables showed that these differences translated into a less than 0.1%-point gap between the groups. The difference in hospital readmission rates was similarly minuscule: 20.4% for patients cared for by first-year physicians in both 2000– 2006 and 2007–2012, compared with 20.1% and 20.5%, respectively, among patients treated by senior physicians.

Taken together, these findings suggest that US residency work hour reforms have not made a difference in the quality of physician training, Jena concludes.

As a way of magnifying any possible gaps in care stemming from a difference in training hours, the researchers looked specifically at outcomes for high-risk patients, in whom even small differences in quality of care would become apparent.

“We looked at patients who were particularly ill. In these cases, one little mistake could mean the difference between life and death,” Jena says. “Even for these sickest patients we found that the reduced training hours had no effect on patient mortality.”

interventional radiologists in the UK. While women currently make up 50% of junior doctors, just 10% of qualified interventional radiologists are female. This pattern also holds true across continental Europe and the USA. The BSIR Women and Diversity committee aims to understand the causes of this discrepancy, and its mission statement is to find ways to “overcome the barriers” to potential female interventional radiologists. At the latest committee meeting, the most obvious barriers were felt to be issues around pregnancy and screening, fertility and screening, and access to flexible or part-time working.

“Definitions of diversity abound”, comments Fiona Miller (London UK). “I see diversity as empowering people by respecting and appreciating what makes them different, in any way, including age, gender, ethnicity, religion, disability, sexual orientation, education, and national origin. The main reward for accommodating diverse colleagues is a wealth of new ideas and approaches to our professional lives. A further benefit of working in a diverse peer group where individuality is respected is [a] better work–life balance for all.”

Elaborating on the decision to create the committee, Miller explains: “In order to attract the best doctors, IR needs to be welcoming and inclusive to all. It was with this in mind that [the] BSIR council decided to create the Women and Diversity committee with time and resource[s] to focus on barriers to interventional radiology recruitment and retention. The precise remit will be determined by the elected group in discussion with council. At the first meeting, clear aims and objectives were defined, the primary aim being the promotion of equality for all in interventional radiology. The first project will be to address the challenges facing women in interventional radiology, followed by other issues including sexual orientation and gender identity, ethnicity and disability.”

In addition to Wah and Miller, the committee consists of three other elected members: chair Ros Ahmad (Leicester), Shilpi Pal (Dundee), and Elika Kashef (London).

Artificial intelligence

Issue 75 | September 2019

Artificial intelligence solution improves clinical trial recruitment Clinical trials are a critical tool for getting new treatments to people who need them, but research shows that difficulty finding the right volunteer subjects can undermine the effectiveness of these studies. Researchers at Cincinnati Children’s Hospital Medical Center (Cincinnati, USA) designed and tested a new computerised solution that used artificial intelligence (AI) to effectively identify eligible subjects from Electronic Health Records (EHRs), allowing busy clinical staff to focus their limited time on evaluating the highest quality candidates.

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he study is published online in JMIR Medical Informatics. It shows that compared to manually screening EHRs to identify study candidates, the system—called the Automated Clinical Trial Eligibility Screener (ACTES)—reduced patient screening time by 34% and improved patient enrolment by 11.1%. The system also improved the number of patients screened by 14.7% and those approached by 11.1%.

Busy emergency departments often serve as excellent locations for clinical trial coordinators to find people who may be good study candidates. According to the study’s lead investigator, Yizhao Ni (Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA), ACTES is designed to streamline what often proves to be an inefficient clinical trial recruiting process that does not always catch enough qualified candidates.

“Because of the large volume of data documented in EHRs, the recruiting processes used now to find relevant information are very labour intensive within the short time-frame needed,” comments Ni. “By leveraging natural language processing and machine learning technologies, ACTES was able to quickly analyse different types of data and automatically determine patients’ suitability for clinical trials.”

from EHRs. It also identifies unstructured information from clinical notes, including the patients’ clinical conditions, symptoms, treatments and so forth. The extracted information is then matched with eligibility requirements to determine a subject’s suitability for a specific clinical trial.

The system’s machine learning component also allows it to learn from historical enrolments to improve its future recommendations, according to the researchers.

Much of the analyses are handled by carefully designed AI algorithms, essentially procedures or formulas that computers use to solve problems by performing a set sequence of specified actions.

Advanced to live clinical setting

A patient at Cincinnati Children’s Hospital

How it works

The system has natural language processing, which allows computers to understand and interpret human language as the system analyses large amounts of linguistic data. Machine learning allows computerised systems to automatically learn and evolve from experience without specifically being programmed. This makes it possible for computer programmes to process data, extract information, and generate knowledge independently.

The automated system extracts structured information such as patient demographics and clinical assessments

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Previously the system was successfully pilot tested in a retrospective study published in 2015 by the Journal of the American Medical Informatics Association. The current study tested the solution prospectively and in real time in a busy emergency department environment, where clinical research coordinators recruited patients for six different paediatric clinical trials involving different diseases.

Using the technology in a live clinical environment involved significant collaboration between data scientists, application developers, information service technicians and the end users, clinical staff.

“Thanks to the institution’s collaborative environment, we successfully incorporated different groups of experts in designing the integration process of this AI solution,” Ni says.

The researchers listed as limitations the small number of clinical trials used in the study, all from a single clinical department. They also pointed to some lingering issues involving the system’s accuracy at interpreting data. These issues will be resolved in future studies through ongoing enhancements to the technologies and also by testing the system in a wider variety of clinical departments, according to the investigators.

Medical ethics

Issue 75 | September 2019

Reflection, confession, and resolution: The ethics of complications in interventional radiology Eric Keller Comment & Analysis Complications are an inevitable component of an interventional radiologist’s practice, says Eric Keller, particularly as a newer specialty with a reputation for pushing medical frontiers. As such, he elaborates on the ethics of procedural complications, and describes how he believes physicians should conceptualise and learn from their mistakes. Keller calls for more research on the ethics of complications in interventional radiology (IR), detailing how the innovation that characterises the specialty could be directed towards reimagining approaches to answering hard-hitting questions.

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ome people consider “errors” and “complications” distinct, in that an error implies a mistake was made, while complications occur even when everything is done correctly. This distinction is helpful from a systems perspective, but these events do not feel very different personally or ethically.1 When a procedure does not go as expected and hurts someone, it violates a basic assumption held by patients and clinicians: doctors heal people. It leaves us with questions and uncertainty that can undermine our relationships with patients and colleagues and leave clinicians asking, “What if I had…?”.

Complications seem particularly personal for interventionalists. When a patient dies on a medical service, people tend to ask, “What happened?”, but when a patient dies on a surgical service, people ask “What did you do?”.2 Although successes define one’s career, it is often responses to shortcomings that defines one’s character.

Complications challenge us to be better and to support those hurt in our efforts to improve. When they occur, we should question what we owe our patients, selves, and colleagues, and to some degree, the answers are similar: reflection, confession, and resolution.

First, we should try to understand why a complication occurred and how to best avoid it in the future. It can be tempting to consider a complication merely as something that happens or attribute the fault to someone or something else, but we should always reflect upon our role in the event. Likewise, it can also be tempting to feel like a failure and let complications paralyse us, but the only interventionalists that do not have complications are those that do not perform procedures. Neither extreme is helpful.

One useful approach for reflection is Charles Bosk’s categorisation of operator errors,2 which is summarised in Table 1 with examples for interventional radiology (IR). Errors of technique or clinical judgement happen to everyone and are easier to improve with more training and experience. However, errors of character (normative or quasinormative errors) are more difficult. In the face of these errors, we should look for deeper causes. Was the interventionalist depressed, burnt out, or overwhelmed by other aspects of life? Is the current practice or career not the right fit? If this is the case, we owe it to our patients, selves, and colleagues to step away and get help.

Once one has reflected upon the cause of the complication, this understanding should be used to provide an explanation

and support to patients, families, and colleagues. For patients and families, complications can undermine trust, which is central to the patient-clinician relationship.3 It is trust that allows people to let us render them unconscious and thread catheters and wires into their bodies. Without this trust, it can be difficult for people to get the care they need, so in the face of complications, we owe it to patients to help rebuild that trust, not just in one clinician, but healthcare in general. Rather than abandoning patients, we should advocate for them by providing information, support, and guidance.4 An apology can also go a long way. Some may worry that an apology will increase the risk of a lawsuit, but research tends to suggest otherwise. Patients that sue tend to be those who did not receive the information or support they felt they deserved.5 Similarly, we should not leave our colleagues to deal with our complications alone. Rather, we should take responsibility for what occurred and partner with them. In IR, referrals networks are important, and complications can weaken these relationships. Just as with patients, we owe our colleagues an explanation and support to rebuild their trust. Colleagues can also be invaluable for stopping a difficult situation from getting worse, and we should have the humility and

We should reflect upon our complications, try to understand what caused them, and give ourselves permission to be human and learn from them.” insight to ask for help when things go awry.6 We can also provide an opportunity for our colleagues to learn from our complications via morbidity and mortality

Table 1: Bosk’s Four Type of Operator Errors

Error

Description

Example

Technical

Well-intended but skills fell short

Taking multiple passes to position an ablation probe in the lung results in a large pneumothorax and hemoptysis

Judgement

Skills were adequate Not checking sufficiently but medical decision for collaterals prior to Y90 making was flawed resulting in poor treatment response

Normative

Lapse in professional character

Ignoring pages about a sick patient to take a nap, resulting in a bad outcome

Quasi-normative

Repeatedly violating the cultural norms of one’s practice

Using a previously accepted UFE protocol that one’s practice has decided should be no longer be used

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conferences. Ideally these should be constructive and supportive rather than whipping posts for subordinates. Again, everyone has complications, and we owe it to our patients, selves, and colleagues to learn from them together.

This approach of reflection, confession, and resolution is not specific to IR, so it is also worth considering some unique aspects of IR culture related to complications. As a newer specialty, there tends to be less data to guide clinical decision making. The specialty has a reputation of being the cowboys and cowgirls of medicine, always willing to try something. We even have an entire forum to celebrate “extreme” cases that could easily end up in morbidity and mortality conferences of other specialties.

This creates a complex relationship with complications. IR has classification systems to measure and report complications but not a robust forum for discussing the cases that did not save the day, and how this relates to our drive for innovation or willingness to push the envelope. Furthermore, discussions of complications tend to be limited to more tangible periprocedural events such as bleeding or infection. There is little work in IR exploring issues of consent, futility, conflicts of interest, or tribalism. Overall, there seems to be a need for a balance; forums to celebrate innovation and to discuss the difficult ethical questions that interventionalists face each day.

In summary, complications and errors are likely to feel similar to interventional radiologists, their patients, and their colleagues. These events contradict expectations and hopes and leave people with uncertainty that can undermine relationships with patients, families, and colleagues. In response, we should reflect upon our complications, try to understand what caused them, and give ourselves permission to be human and learn from them. We can then use this understanding to provide an explanation and support to our patients and colleagues to rebuild trust and rapport with them. On a larger scale, we should also consider developing more research on and forums to discuss ethics in IR. Perhaps IR can develop innovative approaches to the difficult ethical questions we all face as well as the clinical ones.

Eric Keller an interventional radiology resident at Stanford, USA, and has a Master of Arts in Medical Humanities and Bioethics from Northwestern University, Chicago, USA. References: 1. Angelos P. Complications, errors, and surgical ethics.

World J Surg. 2009;33(4):609-11.

2. Bosk CL. Forgive and remember: managing medical failure. 2nd ed. Chicago: University of Chicago Press; 2003. xxv, 276 p.p.

3. Pellegrino ED. Professionalism, profession and the virtues of the good physician. Mt Sinai J Med. 2002;69(6):378-84.

4. Meruelo NC. Mediation and medical malpractice: the need to understand why patients sue and a proposal for a specific model of mediation. J Leg Med. 2008;29(3):285-306.

5. Hickson GB, Clayton EW, Githens PB, Sloan FA. Factors that prompted families to file medical malpractice claims following perinatal injuries. JAMA. 1992;267(10):1359-63.

6. Keller EJ, Crowley-Matoka M, Collins JD, et al Fostering better policy adoption and inter-disciplinary communication in healthcare: A qualitative analysis of practicing physicians’ common interests. PLoS One. 2017;12(2):e0172865.

UK interventional radiology

Issue 75 | September 2019

Vascular Anomalies Special Interest Group brings together a range of specialists this December Jocelyn Brookes

Complex classification

Over the past 30 years, the International Society for the Study of Vascular Anomalies (ISSVA) has met biannually to develop an internationally agreed classification of these perplexing lesions based originally on descriptive characteristics, separating malformations from vascular tumours and defining separate lesions by their phenotypic approximation to arteries, veins, capillaries or lymphatics.

Distinction of high- and low-flow lesions has led to the development of observational treatment classifications guiding specific therapeutic approaches; for example, Houbart (neuro AVM), Yakes (peripheral AVM), and DuboisPuig (peripheral low-flow VM).

Many treatment modalities

Comment & Analysis Vascular malformations have perplexed a plethora of physicians from diverse specialties for decades, writes Jocelyn Brookes.

The British Society of Interventional Radiology (BSIR) has formed a Vascular Anomalies Special Interest Group (VASIG), which met last year for a study day to discuss treatment approaches and outcome measurements. This year, the group welcomes interested specialists to The Royal Free Hospital, London, UK, on 5 December to continue the conversation.

V

ascular anomalies (arteriovenous/vascular malformations [AVM]) and associated syndromes have traditionally formed an esoteric area of endeavour for a small group of interested practitioners whose specialist backgrounds reflect the variety and complexity of the lesions themselves.

These non-neoplastic yet proliferative disorders of vascular tissue differentiation may present at all times of life at unpredictable times of growth, causing pain, bleeding, thrombosis, and local space occupation (such as airway embarrassment), with consequent symptoms varying from trivial to catastrophic and lethal. Most are genetically random, but some are

familial and syndromic.

Multiple interested specialist backgrounds

Presenting in all tissues of the body, superficial vascular malformations (for example, port wine stains) have become of interest to dermatologists and plastic surgeons, with vascular surgeons and, latterly, interventional radiologists attending to deeper tissue vascular malformations whilst neurointerventionalists and surgeons have treated intracerebral ones.

Depending on local interests and referral patterns, specialist centres have developed and dissipated in each generation, usually with the retirement of the central enthusiast of the group.

UK NICE explores extending use of real-world data to inform its guidance The United Kingdom’s National Institute for Health and Care Excellence (NICE) is looking to extend the use of real-world data that will help inform its independent committees that produce its guidance.

THE INSTITUTE ALREADY makes use of a wide range of published scientific evidence for its

Treatment methods range from excision surgery to arterial embolization, sclerotherapy to percutaneous coagulation. For high-flow AVM lesions, the search for the elusive, transformative “nidus” absorbs practitioners with an intensity as if on a quest for the Holy Grail.

But things are changing in this challenging field.

Bring your challenging cases [to discuss at VASIG 2019].”

Multidisciplinary approach

Long-term (officially incurable) chronic vascular lesions with (traditionally) heroic surgical complication rates need a specialist multidisciplinary approach involving appliances, nurse specialists, psychologists, palliative care, haematology, and, more recently, genetics and pharmacology all working together to care for this challenging group of patients.

guidance for the National Health Service (NHS) on health technologies and its advisory guidelines, which demonstrate best practice for diagnosing and managing a range of conditions.

Now, NICE proposes to extend its use of data from sources including: Hospital records of operations Registries that collect data on how particular treatments are used Surveys of people using services Data collected on national trends, such as how many people have a condition If approved, NICE believes it will help the institute further improve its guidance, update it more quickly, and provide a better understanding of the impact it has for people accessing health and social care services. A consultation has begun in NICE’s Statement of Intent, which set out the ways in which the institute already uses data in its work and how it would like to extend this in the future.

The consultation on the NICE data and analytics Statement of Intent runs from 13 June to 13 September.

NICE conclude their Statement of Intent thus: “NICE welcomes the opportunity to continue our

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Exciting new developments

Recent exciting developments in the understanding of errors of genetic signalling pathways in endothelial cell proliferation and corresponding pharmacological interventions are revolutionising the approach to VM care. Biomarker technologies and sophisticated imaging modalities are now casting light, logic, and sense onto this dark and perplexing area with very real benefits to our patients.

Increasing professional interest

For the past five years, the AVM session at the Charing Cross Symposium (CX; London, UK) has begun to attract larger audiences and, with the growth of image-guided embolosclerotherapy as the most popular modality of treatment, the British Society of Interventional Radiology (BSIR) has drawn together the disparate groups interested in vascular malformations to search for commonalities of approach and measurements of outcome.

Come to the VASIG meeting on 5 December 2019

The Vascular Anomalies Special Interest Group (VASIG) met last year for a study day at The Royal Free Hospital, London, when over 60 delegates of all specialty backgrounds attended.

Delegates brought challenging cases to discuss with colleagues from all over the UK and the Republic of Ireland.

Offered gratis, the meeting rewarded its participants with five continuing professional development (CPD) points and was universally applauded as interesting, inspiring, and relevant to practice.

The VASIG study day will be held on 5 December this year at The Royal Free Hospital, London. Local accommodation can be arranged. Bring your challenging cases.

Jocelyn Brookes is a consultant endovascular radiologist at The Royal Free NHS Foundation Trust and The London Clinic, London, UK.

We look forward to engaging with other organisations that have expertise in data analytics to explore areas of shared interest.” well-established practice of translating evidence into practical guidance and advice, and to expand our methods and processes to enable more extensive and effective use of broader sources of data.

“We acknowledge that there are challenges in expanding our use of data and analytics, but we believe that the potential benefits to health and social care providers and users of their services outweigh the risks.

We look forward to engaging with other organisations that have expertise in data analytics, to explore areas of shared interest and work together to improve health and social care. We will seek to reduce barriers and set up frameworks to enable this work to succeed.”

SIR meeting

Issue 75 | September 2019

“Let’s connect in Seattle!”

Be heard. Be seen. Get published!

The Society of Interventional Radiology (SIR) invites practising physicians, early career professionals, research scientists, clinical associates, trainees and medical students to submit original research for possible presentation during the society’s Annual Scientific Meeting, 28 March–2 April, 2020, in Seattle, USA. Online abstract submission is open at sirmeeting.org until 5pm ET on 26 September, 2019.

“INTERVENTIONAL RADIOLOGY is constantly redefining the landscape of minimally invasive, image-guided treatments. You can play a role in this evolution by sharing your ideas, innovations and state-of-the-art technology at the SIR 2020 Annual Scientific Meeting. SIR 2020 is the place to see what is at the forefront of the specialty that will enable us to continue to provide the best patient care,” says SIR 2020 scientific chair Baljendra S Kapoor, an interventional radiologist at the Cleveland Clinic, Cleveland, USA. “The SIR Annual Scientific Meeting highlights collaboration in interventional radiology and addresses bold strides in clinical practice. I invite you to join us in Seattle and share your research and expertise with attendees from around the world.”

SIR details how to get involved: “Submissions may be accepted for oral or poster presentation for scientific abstracts and traditional paper posters for educational exhibits. Please note, single-case reports will not be accepted.

Original scientific research abstracts accepted for oral presentation, ePoster

Photos from previous SIR meetings

or traditional poster presentation will be published in the supplement to SIR’s flagship Journal of Vascular and Interventional Radiology (JVIR), and on jvir.org, and will be a citable reference.

“Selected abstracts will be designated as ‘Distinguished’, ‘Featured’ or ‘Abstract of the Year’. Additionally, national and international consumer and trade media will report on ground-breaking research presented at SIR 2020.”

SIR 2020 is expected to attract more than 5,000 attendees from around the globe to Seattle, a city known for germinating new technologies and bold scientific thinking. Researchers who are accepted will have the opportunity to grow the field of imageguided interventions by sharing their discoveries, device and procedure innovations, clinical outcomes, and breaking research in areas that address many of today’s most challenging medical problems, including cancer, vascular disease, and men’s and women’s health.

According to SIR, in 2020 the meeting will include lecture-based didactic sessions; centrepiece plenaries that

will inspire and educate; Angio Clubs, a series of case-based workshops; SIRConnectLive, a unique town-halltype session that promotes interactive learning; self-assessment CME (SACME) sessions, which help fulfil maintenance of certification (MOC) requirements; hands-on workshops and much, much more.

High-level scientific abstract presentations are featured during the meeting’s scientific sessions, where attendees will learn about current clinical trials, technical innovations, and the basic science shaping the foundation of the specialty.

Abstracts presented during the scientific sessions span a wide breadth of categories, including arterial interventions; venous interventions; nonvascular interventions; dialysis interventions; education and training; practice management; health care policy; and quality improvement.

SIR Expo

The SIR 2020 exhibit hall at the Washington State Convention Center is open to all registered attendees and

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guests with a badge. Attendees should watch for special events and hands-on sessions at select booths. Throughout the meeting, attendees will be encouraged to attend “Compelling Conversations,” a series of informal, popular question and answer sessions on timely topics, held at SIR Central in SIR Expo.

About Seattle

Seattle is a world-class metropolis set within beautiful, natural surroundings, offering the best of an urban lifestyle while embracing the outdoors. Many of Seattle’s top visitor attractions are within a few blocks of the Washington State Convention Center, including the Pike Place Market, Seattle Art Museum, ferries, world-class restaurants, and a historic theatre district. Three national parks lie within a two-hour drive of Seattle and the city is a gateway to the San Juan Islands, Washington Wine Country, and British Columbia.

About the Society of Interventional Radiology

The Society of Interventional Radiology is a non-profit, professional medical society representing more than 8,000 practising interventional radiology physicians, trainees, students, scientists and clinical associates, dedicated to improving patient care through the limitless potential of image-guided therapies. SIR’s members work in a variety of settings and at different professional levels—from medical students and residents to university faculty and private practice physicians.

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IR curriculum

September 2019 | Issue 75

CIRSE updates and expands its interventional radiology curriculum for medical students The Cardiovascular and Interventional Radiological Society of Europe (CIRSE) has released a newly revised interventional radiology (IR) curriculum for medical students. The original curriculum from CIRSE, published in 2012, was five pages long; this most recent version is considerably longer, at 24 pages.

A STATEMENT FROM CIRSE reads: “IR has grown continuously over the past decades, with interventional treatments being applied to an everincreasing number of conditions. Now more than ever, young physicians are showing interest in pursuing a career in IR—an extremely interesting field combining state-of-the-art procedures with clinical practice, patient interaction and multidisciplinary teamwork.

“Due to its innovative nature, patientcentred treatment approach and the everincreasing applications of interventional procedures, IR has become one of the most interesting career choices for medical students. In order to help students make an informed decision, CIRSE has released a newly revised IR Curriculum for Medical Students describing the most important procedures performed by interventional radiologists.”

It goes on to say that the updated IR curriculum enables medical students “to find out more about IR’s key areas and the most common clinical conditions treated by interventional radiologists”.

Christoph Binkert (Institute of Radiology and Nuclear Medicine, Kantonsspital, Winterthur, Switzerland) is the editor-in-chief of the document, and he founded and chaired a CIRSE taskforce dedicated to updating this second edition of the curriculum.

Five editors worked with him on the revised publication: Roberto Cazzato (Department of Interventional Radiology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France), Jan Jaap Janssen (Academisch Medisch Centrum, Amsterdam, The Netherlands), Gregory Makris (Oxford University Hospitals NHS Foundation Trust, Oxford, UK and chair of the British Society of Interventional Radiology trainee committee), Arash Najafi (Kantonsspital, Winterthur, Switzerland), and Fatemeh Sakhinia (Royal Stoke University Hospital, Stoke, UK).

Speaking to Interventional News, Binkert says that is timely to provide an updated curriculum now, as “IR has changed markedly, and has become a true clinical specialty!”. However, he adds that

“career planning starts early (not many residents change specialty); unfortunately, in many medical schools, IR is not really taught as a dedicated specialty”.

There have been several additions

to the revised document. Although the original curriculum makes no mention of embolization, this latest one includes a dedicated section in the “Vascular IR” chapter on embolization for benign conditions, with reference to uterine fibroid embolization, prostate artery embolization, gastrointestinal bleeding, and gonadal vein embolization. In the “Interventional oncology” chapter, liver malignancy embolization is also included in the revised curriculum for the first time. The updated guidelines also include a subsection on access, which is new from the previous report, and an expanded section on musculoskeletal interventions.

Binkert comments on these key revisions: “In order to make the curriculum more reader-friendly to medical students, we not only changed the format to include bullet pointed lists, but also added more of a disease focus, with increased detail and discussion on clinical presentation, imaging, IR treatments, and follow-up. We hope that this format will help an interested medical student gain a clearer understanding of what modern interventional radiology is all about. In addition to the curriculum, short videos will be available to explain interventional radiology to medical students within two minutes.”

“I think the combination of clinic work, imaging and [performing the] procedures is very appealing to many young doctors”, says Binkert of the attraction interventional radiology holds for medical students.

Market watch

Issue 75 | September 2019

Clinical News TARGET BP I trial enrols its first patient

Razavi, an interventional radiologist at St Joseph Hospital in Orange, USA, and lead investigator of the SAVE-US study.

“I am eager for the system’s commercial approval, and look forward to offering a reliable and repeatable solution to patients with varying occlusion types, halting the devastating impact of central venous occlusive disease.”

Of the 30 patients enrolled in the US IDE SAVE-US trial, 90% met both the primary and secondary efficacy endpoints of facilitated central venous access by the Surfacer system. On average, central venous access was achieved in approximately 12 minutes, despite a more complex patient population comprised largely of Type 3 and 4 occlusions (three or more occluded vessels).

“The Surfacer system passed the SAVE-US study with flying colours, confirming the system is a safe, viable option for achieving right-sided central venous access, preserving secondary central veins,” comments Ehab Sorial (Division of Vascular Surgery, Stanford, USA and the Santa Clara Valley Medical Center, San Jose, USA), the study’s second highest enroller. Sorial first learned about the Surfacer system while working alongside John Gurley, the system’s inventor, for over a decade at the University of Kentucky, Lexington, USA. “This is a highly anticipated treatment that gives physicians a safe and effective alternative to other less efficacious treatments with higher complication rates. I am looking forward to its commercial approval and implementing it into my day-to-day practice.”

Bluegrass Vascular Technologies anticipate that the Surfacer system will be commercially available to physicians in 2020.

Surfacer

Large real-world study supports UroLift’s effectiveness in treating BPH symptoms

The first patient has been randomised in the TARGET BP I trial at the Piedmont Heart Institute in Atlanta, USA, to investigate the use of the Peregrine System Kit (Ablative Solutions) in renal denervation.

Target BP I is a blinded, randomised sham-controlled study that is evaluating the safety and efficacy of the system in the treatment of patients with uncontrolled hypertension who are taking two to five anti-hypertensive medications.

The company announced the trial’s commencement in a press release, which explains that the TARGET BP I trial and the ongoing European TARGETBP OFF-MED trial are part of the TARGET BP clinical trials programme, and are designed to evaluate the safety and efficacy of the Peregrine System Kit when used to treat patients with uncontrolled hypertension. The system is comprised of a patented infusion catheter and dehydrated alcohol.

David Kandzari (Piedmont Heart Institute, Atlanta, USA) co-principal investigator of the TARGET BP I trial, comments in the release: “It is exciting to initiate this important trial to evaluate the Peregrine System Kit for the treatment of patients with uncontrolled hypertension. More than half of those treated with antihypertensive medications do not achieve their target blood pressure, so there is a great need for improved therapeutic options.”

SAVE-US pivotal trial completes enrollment and has positive clinical results

The SAVE-US (Surfacer system to facilitate access in venous occlusions— United States) pivotal trial has completed enrollment. The SAVE-US trial is evaluating the safety and efficacy of the Surfacer Inside-Out access catheter system (Bluegrass Vascular Technologies) in thirty patients across seven US centres, and demonstrated positive clinical results by meeting its primary and secondary endpoints.

According to a press release, the Surfacer system is a novel approach to achieving right-sided, upper body central venous access in patients with upper body venous occlusions or other conditions that preclude central venous access by conventional methods.

“I am quite encouraged by the highly positive results demonstrated by the Surfacer system,” states Mahmood

UroLift

Teleflex received positive results for a multicentre study reaffirming the safety and effectiveness of its minimally invasive UroLift system for the treatment of benign prostatic hyperplasia (BPH) in real-world patient populations.

These were published in the Journal of Endourology.

The multicentre, retrospective study examined the results of 1,413 consecutive

patients who received the UroLift system for treatment of lower urinary tract symptoms due to BPH. The trial took place over a period of two years across 14 sites in North America and Australia.

The study investigators set out to determine whether clinical outcomes are consistent with those found in controlled studies, and found that they were.

Data published from the study show that patients from multiple subgroups treated with the UroLift system experienced improvements in International Prostate Symptom Score (IPSS) and Quality of Life (QoL) score: Consistent with the previous LIFT study, symptoms improved significantly from baseline at all follow-up timepoints through two years, and most perioperative adverse events were mild to moderate, resolving by four weeks.

In a cohort-matched comparison to LIFT study patients with moderate– severe symptoms (IPSS≥13), symptom improvement was similar at all timepoints.

Of the 165 patients in retention at baseline, 83% became catheter-free by one-month postprocedure, and 87% were catheter-free by the end of the study; IPSS scores were similar to non-retention patients.

In the 73 patients with prior prostate cancer treatment, mean IPSS improved at all timepoints, with no significant difference in adverse events of interest compared to other patients.

IPSS improvement was similar regardless of prostate volume (<30cc; 30cc to <80cc; ≥80cc).

“Not only are the real-world results from this large, multicentre study consistent with the LIFT study, this study also provides data in populations of patients who were not studied in the LIFT study but are seen in a real-world clinic setting,” says Gregg Eure, urologist at Urology of Virginia (Virginia Beach, USA), a lead investigator and co-author of the study.

“These findings should give urologists and patients the confidence to adopt the UroLift system within the broader BPH population.”

The randomised LIFT clinical trial demonstrated that treatment with the UroLift system provides patients with rapid and durable symptom relief. The procedure demonstrated an excellent safety profile and preserved sexual function.

UroLift is a minimally invasive technology cleared by the US Food and Drug Administration (FDA) for treating lower urinary tract symptoms due to BPH. The UroLift permanent implants, delivered during a minimally invasive transurethral outpatient procedure, relieve prostate obstruction and open the urethra directly without cutting, heating, or removing prostate tissue.

Teleflex acquired NeoTract, the privately-held medical device company that developed and commercialised the UroLift system, in Autumn 2017 in a transaction valued at up to US$1.1 billion.

FLEX vessel prep system data show key findings, including luminal gain

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New data presented at the 20th annual New Cardiovascular Horizons (NCVH) conference (29–31 May, New Orleans, USA) show positive results for VentureMed Group’s FLEX VP system.

The FLEX iDissection study utilised intravascular ultrasound (IVUS) to assess the reduction in the rate and severity of dissections in peripheral arteries when the FLEX vessel prep system (VentureMed Group) was used prior to angioplasty.

Fifteen patients were evaluated by angiogram and IVUS following treatment of femoropopliteal de novo or no-stent restenosis with the FLEX VP system and percutaneous transluminal balloon angioplasty (PTA). The patients had an average median baseline percentage stenosis of 77% and an average lesion length of 64±33mm; 40% had moderate/ severe calcified vessels (PACSS score≥3); 40% were diabetic. Claudication was present in 73% of the patients.

Angiogram and IVUS images were obtained at baseline, post-FLEX VP system, and post-adjunctive PTA to evaluate the presence and grade of dissections. There were significantly fewer new dissections, as well as lower gradations in the circumference and depth patterns of new dissections, post-FLEX VP system and adjunctive PTA. The majority of new dissections postPTA, following vessel preparation with the FLEX VP system, involved mostly the intima, the innermost layer of the vessel (78.4%) and with a circumference <180° (81.1%). Vessel preparation involving only the layers superficial to the internal elastic lamina may prevent restenosis.

“Dissections are grossly underappreciated on angiogram when compared with IVUS. PTA causes dissections and stretching of the vessel to restore blood flow. However, the severity and depth of the dissections can contribute to restenosis,” comments lead investigator Nicolas W Shammas, (Midwest Cardiovascular Research Foundation, Davenport, USA). “This is a positive signal, as these results showed a low rate of dissection after using the FLEX VP system, with the majority of those dissections being lesser in depth and circumference.”

Also at NCVH, real-world data of 443 femoropopliteal cases reported from 104 operators in 70 health systems treating lesions of varying lengths (less than or equal to 8mm or greater than 8mm) were presented.

Speaking of this comparative review of the FLEX VP system, Jason A Yoho (Heart and Vascular Institute of Texas, San Antonio, USA) says: “These data highlight the importance of the unique FLEX VP mechanism of action that provides acute luminal gain and improved vessel compliance to reduce PTA balloon opening pressures leading to meaningful clinical results. These real-world data on the use of the FLEX VP system is clinically relevant and important as we continue to evaluate options that may help patients achieve better clinical outcomes.”

Market watch

Issue 75 | September 2019

Industry News

Boston Scientific signs medical technology alliance with Mayo Clinic

Medical devices manufacturer Boston Scientific has partnered with Mayo Clinic, a non-profit academic medical centre, to launch an accelerator focused on medical solutions for diseases with unmet clinical needs.

Named Motion Medical, the new 1,800ft² venture will receive funds from partners over three years to develop new medical technology and minimally invasive therapies.

Motion Medical research facilities will be located in the Discovery Square research district’s bioscience centre called One Discovery Square in Rochester, USA. Boston Scientific and Mayo Clinic have been working together for approximately 10 years for the development of medical devices and technologies across interventional cardiology, neuromodulation and urology therapeutic areas, among others.

To date, the companies have submitted eight patent applications and partnered on two first-in-human clinical trials, according to Mayo Clinic.

Boston Scientific develops a variety of medical solutions for endoscopy, rhythm management, interventional cardiology, peripheral interventions, neuromodulation, urology and pelvic health.

In November last year, the company signed an agreement to buy BTG for £3.3bn. BTG has three main businesses and Interventional Medicine is said to be the largest.

The acquisition is expected to help boost Boston Scientific’s capabilities in cancer and pulmonary embolism.

FDA notifies BD that Lutonix paclitaxel balloon PMA request for below-the-knee “not approvable in current form” The US Food and Drug Administration (FDA) have denied BD premarket approval (PMA) for the company’s Lutonix drug-coated balloon (DCB) in the treatment of peripheral arterial disease (PAD).

Speaking in the company’s third quarter conference call on 6 August, BD CEO Vincent Forlenza told analysts: “Regarding our FDA, PMA submission for Lutonix below-the-knee [BTK], as you are all aware, we have been working with the FDA in a collaborative review

process. Subsequent to the FDA Advisory Committee meeting on paclitaxel, the statutory review time for our BTK PMA submission concluded, and the FDA notified us that our PMA was not approvable in its current form.

“While this determination was based on the clinical evidence provided to-date, we continue to review, collaborate and align with the FDA on the path forward regarding our submission, including the need to potentially provide additional clinical data.

“As a result, the approval process timeline has extended out from our previous expectations and we no longer expect approval this calendar year. We will keep you informed as we work with the FDA and make further progress.”

Paclitaxel devices have come under regulatory scrutiny in the last eight months, following the publication of a meta-analysis in the Journal of the American Heart Association (JAHA) by Konstantinos Katsanos (Patras, Greece) and colleagues reporting an increased association of death when paclitaxel devices are used in the lower leg. The FDA analysed all available clinical randomised controlled trials or single-

arm registries conducted with agencyapproved devices with at least two year follow-up. The investigation compared drug-eluting or coated devices with noneluting or coated devices.

At two years, the observed mortality rates for the paclitaxel-coated device group were higher for the Zilver PTX (Cook Medical) trial, Levant 2 (evaluating BD’s Lutonix DCB), and IN.PACT SFA I and II trials (looking at Medtronic’s Admiral DCB) in the FDA’s own analysis.

On the same call, the company reaffirmed its full-year revenue and earnings forecasts, and reported quarterly revenues of US$4.35 billion for the third fiscal quarter (which ended 30 June this year). According to a BD press release, this represents an increase of 1.7% over the prior-year period. The company state that on a comparable, currency-neutral basis, revenues increased 5.7% over the prior-year period.

Medtronic partners with Viz.ai to accelerate adoption of new AI software Medtronic and Viz.ai have partnered to accelerate the adoption of Viz.ai’s new technology, which helps synchronise stroke care and decrease time to treatment, potentially improving outcomes for patients.

Viz.ai’s technology uses artificial intelligence (AI) to identify suspected

large vessel occlusion (LVO) strokes and automatically notify specialists. The Viz.ai software connects to hospital computed tomography (CT) scanners and alerts stroke specialists within minutes that a suspected LVO stroke has been identified, sending the radiological images directly to their smart phones where they can be viewed. Viz.ai enables a physician to provide the patient with the treatment they need as quickly as possible.

“Medtronic is an innovative company focused on therapies that extend life and restore health,” says Chris Mansi, neurosurgeon, co-founder and CEO of Viz.ai. “As the largest medical device company in the world, Medtronic is an ideal partner to help physicians access Viz.ai’s cutting-edge technology to ensure as many patients get the care they need as quickly as possible.”

Stroke is a serious and time-sensitive medical condition that requires emergency care and can cause lasting brain damage, long-term disability and death. A stroke occurs if the flow of oxygen-rich blood to a portion of the brain is blocked. When this happens, two million brain cells die every minute. It is the number-one cause of disability in the USA and the leading cause of death outside of the USA. “Viz.ai allows clinicians to receive an alert for suspected LVO’s and the corresponding visual data” comments Elad Levy, chairman in the Department of Neurosurgery with the University at Buffalo’s Jacobs School of Medicine and Biomedical Sciences and medical director of Neuroendovascular Services at Gates Vascular Institute. “The combination of AI powered alerts, mobile image viewing, and HIPAA compliant communication facilitates synchronisation of stroke care with great potential to impactfully reduce doorto-needle time and help an increased number of patients.”

Every two minutes someone in the USA has an LVO, but only an estimated 15% receive a potentially lifesaving mechanical thrombectomy, a minimallyinvasive procedure that removes blood clots. A Viz.ai study in two centres showed that in 95.5% of true positive cases, its technology alerted the stroke specialist earlier than the standard of care, saving an average of 52 minutes.

“We are excited about this partnership because Viz.ai’s technology has the potential to significantly reduce the time it takes for patients suspected of LVO stroke to receive the care they need,” says Stacey Pugh, vice president and general manager of Medtronic’s Neurovascular business, which is part of the Restorative Therapies Group at Medtronic.

“Viz.ai’s software coupled with our network is going to increase access to needed therapies.”

Through this agreement, Medtronic will distribute Viz.ai’s existing LVO detection and triage software services, which are currently permitted for marketing in the US. It was the first clinical decision support software designed to analyse CT results that may notify providers of a potential stroke in their patients cleared by the US Food

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and Drug Administration (FDA). The technology is available in over 200 hospitals, with the goal of making Viz.ai available to every stroke centre in the country.

Mentice and Siemens Healthineers bring a virtual patient to the angiosuite

Siemens Healthineers and Mentice AB have announced that they are collaborating to fully integrate Mentice’s VIST virtual patient into the Artis icono angiography system from Siemens Healthineers.

According to a press release, the VIST virtual patient thus becomes a fully integrated simulation solution for the angio-suite. The global partnership between the two companies will allow interventional radiologists, neuroradiologists, and cardiologists to perform vascular and cardiac interventions on a virtual patient inside the angio-suite.

“With an ever-increasing complexity of new interventional procedures, our customers strive to acquire and retain procedural skills while optimising their performance and improving patient

safety. The Artis icono angiography system equipped with a VIST virtual patient will make it possible to train new interventional procedures directly in the angio room,” says Michael Scheuering, head of Interventional Radiology at Siemens Healthineers.

“The VIST virtual patient integration into the Artis icono angiography system will open new opportunities for clinical teams to improve their overall performance, drive operational efficiency, and more importantly, help improve patient outcomes. By using the Artis icono system on the VIST virtual patient, clinicians may now explore new interventional procedure methods and experience the use of new medical devices while reducing clinical training on actual patients and eliminating exposure to radiation,” comments Göran Malmberg, CEO at Mentice.

Interventionalists may now perform simulated cardiac and vascular procedures by using the Artis icono controls to angulate the C-arm, move the angiography table, use the foot pedals, and review fluoroscopic images on the Artis icono screens while deploying actual medical devices in a radiationfree environment. The integrated solution will allow clinicians to perform procedures either by using Mentice’s library of patient cases or by importing actual MR and CT patient data for case training and rehearsal. Transesophageal echocardiography (TEE), intravascular ultrasound (IVUS), optical coherence tomography (OCT), and fractional flow reserve (FFR) procedures are also available.

Market watch

Issue 75 | September 2019

Product News

Lutonix

BD receives FDA approval for expansion to drugcoated balloon product line

The US Food and Drug Administration (FDA) has approved expanded sizes of the Lutonix 018 drug-coated balloon (DCB) to treat long superficial femoral artery lesions in patients with peripheral arterial disease.

According to a press release, the Lutonix 018 DCB provides clinicians with a variety of longer sizes allowing more options for 7mm diameter vessels. This includes four new lengths: 80mm, 100mm, 150mm and 220mm.

The Lutonix 018 DCB is designed to perform over small guidewires, reduce guidewire exchanges and enable alterative access sites.

Lutonix 018 DCB is available in the USA, and is currently undergoing the regulatory approval process in Europe.

Boston Scientific launches new stent in the USA for venous obstructive disease

Boston Scientific has won FDA approval for its Vici Venous Stent System for the treatment of iliofemoral venous obstructive disease.

The device received CE mark in 2013, and was developed by Veniti, one of the many companies Boston Scientific acquired last year. The company paid US$108 million for Veniti last August, and FDA approval of the Vici Stent System satisfies one of the milestones for up to another US$52 million.

Iliofemoral venous obstructive disease occurs when the flow of blood through the veins located deep in the pelvic region becomes blocked by a blood clot or compressed by anatomical anomalies. Endovascular treatment for venous obstructive disease is focused on restoring the normal flow of blood from the legs back to the heart. Because the iliofemoral veins are located deep in the pelvis, they may be subject to significant crushing forces from other anatomical

Vici Venous Stent System

structures such as the right common iliac artery. To help solve for this, the Vici stent system was designed to be uniformly strong and crush resistant, capable of restoring blood blow by creating a cylindrical, patent vessel.

FDA approval was supported by data from the VIRTUS study, a prospective, multi-centre, single-arm study with 170 patients. The VIRTUS study evaluated the stent in relation to pre-defined objective performance goals in patients with a clinically significant obstruction in the illiofemoral venous outflow tract. It met its primary safety and effectiveness endpoints.

According to Mahmood Razavi (St Joseph Hospital, Orange, USA), venous obstructive disease can cause quality of life issues without optimised treatment options.

“With the approval of the Vici stent, clinicians now have access to a stent that was purposely developed and engineered to resist the vessel compression and anatomical tortuosity commonly found within the iliofemoral venous system, enabling our ability to deliver best outcomes for our patients,” Razavi says.

Boston Scientific note that venous obstructive disease affects nearly 40% of the US population and can be caused by conditions such as deep vein thrombosis, post-thrombotic syndrome, and compressive diseases such as MayThurner syndrome. In patients with venous obstructions, blood may pool in the legs, resulting in pain, swelling, and skin ulcers.

Centerline Biomedical’s surgical positioning system gets FDA clearance

The FDA has granted 510(k) clearance to Centerline Biomedical’s IntraOperative Positioning System (IOPS), a device used in endovascular procedures to provide 3D visualisation.

The non-radiation-based surgical navigation system uses anatomical mapping algorithms and electromagnetic tracking to give surgeons 3D colour visualisation and guidance during procedures.

The holographic system offers an alternative to X-ray fluoroscopy, which exposes surgeons and operating room staff to potentially dangerous radiation.

FDA clears the only radiation reduction technology that integrates into mobile C-arms

ControlRad has announced that the US Food and Drug Administration (FDA) has granted 510(k) clearance for its ControlRad Trace. The company has initiated its commercial launch.

The ControlRad Trace is the only technology that can be integrated into existing mobile C-arms to reduce radiation in any fluoroscopic imaging

procedure.

“Radiologists and our teams have grave concerns about the long-term effects from radiation exposure,” says John A Carrino, vice chairman of Radiology, Hospital for Special Surgery (New York, USA). “I am excited that new technology for mobile C-arms is now available because it has the potential to drastically improve our radiation safety while maintaining image quality so we can continue to effectively diagnose and treat our patients. I believe these new products should become the standard of care for fluoroscopic procedures.”

Fluoroscopically guided procedures with C-arms have allowed for major advances in treating countless diseases, however they expose patients and medical staff to ionising radiation, which may increase a person’s lifetime risk of developing cancer. For example, an interventional fluoroscopy procedure is roughly equivalent to the adult effective dose of between 250–3,500 chest X-rays.

ControlRad Trace

“Radiation from C-arm procedures may increase the risk of brain cancer, cataracts, strokes and atherosclerosis,” says Guillaume Bailliard, ControlRad CEO. “It is our mission to dramatically reduce these life-altering radiation health risks to medical personnel and patients. This FDA clearance for ControlRad Trace allows us to provide our valuable radiation reduction technology to all mobile C-arm users looking to provide a safer environment without compromising patient care.”

With its proprietary semitransparent filter, tablet and image processing technology, the ControlRad Trace solution can be retrofitted on existing C-arms, which, according to a press release, reduce the barrier to adopting the technology in order to reduce unnecessary radiation by up to 89%, without compromising image quality in the region of interest and overall workflow. The medical staff draws a region of interest on a ControlRad tablet, which in real-time optimises image quality in the region of interest while reducing unnecessary radiation in the periphery.

Embolx extends the sniper balloon occlusion microcatheter family with launch of new K-tip design

Embolx has announced the commercial availability of the new Sniper K-tip in the USA and Europe. The sniper balloon occlusion family of microcatheters now includes the new K-tip, a 45-degree

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angled tip designed to enhance tracking and vessel access capabilities. This extension to the sniper family offers physicians the ability to customise treatment with an array of different balloon microcatheter lengths and tip options.

“The Sniper K-tip marks the first preshaped tip on a balloon microcatheter and has shown remarkable performance in accessing target locations previously too challenging to reach,” says Michael Allen, president and CEO of Embolx.

“For interventional radiologists, the K-tip provides an additional option to handle complex anatomies so they can achieve improved results.”

The sniper microcatheters are now available with two tip options—straight tip or K-tip—and in three lengths: 110cm, 130cm and 150cm. The K-tip offers interventional radiologists better control and torqueability through hardto-navigate vessels to deliver targeted embolization treatment, a press release states.

“Sniper has changed the way I do both chemoembolization and radioembolization. With sniper, I am able to infuse a higher volume of embolic agent into a smaller, focused area. This allows me to treat tumours more aggressively with less impact on normal liver tissue,” comments Brian Kouri, associate professor in interventional radiology at Wake Forest Baptist Medical Center, Winston-Salem, USA. “My initial case experience with sniper’s new K-tip design has been great in every respect. It allowed me to access some pretty small vessels quickly and navigate an over 180-degree vessel turn into the right gastric artery. The tip performance is impressive as it easily tracks inside vessels and torques on a one-to-one basis allowing the sniper to make sharp vessel turns.”

The sniper microcatheter alters blood flow dynamics by controlling pressure to increase therapeutic agent delivery into target areas. It is currently used for the treatment of cancerous tumours in the liver and other organs, enlarged prostate (benign prostatic hyperplasia), and uterine fibroids. This therapy allows the delivery of drugs and embolic agents to only targeted treatment areas, while protecting surrounding healthy tissues.

New indication approved for Guerbet’s Lipiodol Ultra Fluid

A new indication for Lipiodol Ultra Fluid (Guerbet) has been approved in Switzerland and in India for chemoembolization (cTACE) of tumours in adults with known intermediate-stage hepatocellular carcinoma (HCC).

HCC is the most common primary liver cancer and is the fourth leading cause of annual cancer death worldwide.

“Guerbet is proud to have received approval for this new indication for Lipiodol Ultra Fluid. This is evidence of our commitment to making cTACE available to as many HCC patients as possible,” says Thomas Bonnefont, Guerbet’s vice president for Interventional Imaging. “Development