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Percutaneous AV Fistula Creation using Ellipsys and WavelinQ
September 27, 2021

Author(s):
Griffin McNamara
Johnathan Neshiwat
Chris Childers
Jonah Adler

Editor(s):
Tushar Garg, MD

History
Dialysis treatment for chronic kidney disease was first developed by Dr. Willem Kolff in 1943, after various iterations and advances its availability began to grow in 1962 after which it has become a mainstay treatment for patients with chronic kidney disease [1,2]. It is estimated that, in 2021, 15 percent of adults in the United States (approximately 37 million people) have chronic kidney disease, of which 661,000 individuals have renal failure, and 468,000 individuals require dialysis [3,4]. There have been a number of advancements in dialysis treatment since its advent; most notably, the creation of arteriovenous fistulas (AVF) for chronic venous access in 1966 [5].

AVF formation is traditionally performed by vascular surgeons by creating radiocephalic, brachiocephalic, or brachiobasilic transpositions and suturing the anastomoses. According to Dr. Dheeraj Rajan, division head and professor of vascular and interventional radiology at the University of Toronto, “the basic technique of creating an AV fistula has not changed considerably since 1966 when initially described by Brescia and Cimino. The sutured anastomosis also has not significantly changed since initially described by Carrel in 1902” [6]. As a result, patients often require post-creation interventions such as in order to maintain patency and facilitate proper maturation of the fistula. For example, in a 2018 study, patients receiving endovascular AVF placement were found to have an event rate per patient-year of 0.74, compared to 7.22 in patients who received surgical intervention (P<.0001) [7].

In recent years, the FDA has approved two new methods for AV fistula creation using a percutaneous approach. These include the WavelinQ (Beckton Dickinson, NJ) and Ellipsys (Avenu Medical, CA) endovascular arteriovenous fistula devices that use radiofrequency and thermal technologies, respectively, to fuse vessels. In 2014, William Cohn, M.D., vice president and director of Johnson and Johnson Center for Device Innovation at TMC, presented a prototype of the Wavelinq endoAVF System, known as everlinq endoAVF system [8]. In 2018, everlinq was approved by the FDA for marketing alongside the Ellipsys endovascular AVF system [9] (5). Several follow-up studies since the introduction of these technologies have shown that they are associated with fewer additional procedures in the 12 months following the initial procedure, suggesting better outcomes and decreased cost [10,11]. Implementation of endovascular AVF placement is also associated with more rapid maturation of the AVF and decreased time to initiation of dialysis [12].

Current
These two techniques are performed by vascular specialists who use a wire to advance a probe in retrograde fashion through the superficial veins in the upper extremity into the radial/ ulnar artery. A probe is then advanced and uses magnets to align the artery and vein and uses thermal energy or radiofrequency to fuse the arteriovenous anastomoses to create the fistula. This technique has favorable outcomes when compared to the traditional surgical technique. First, this is a minimally invasive procedure, and results in minimal scarring and tissue damage around the fistula. Additionally, the formation of a “side by side” anastamoses lessens stress from blood flow, decreases the risk for vessel wall thickening, and has favorable effects on blood flow [15].

WavelinQ:
WavelinQ was given 510(k) clearance by the FDA in 2018 [13]. WavelinQ is indicated for the creation of an arteriovenous fistula using the concomitant ulnar artery and vein in patients who have chronic kidney disease and need hemodialysis. A minimally invasive approach using WavelinQ is achieved using magnets. WavelinQ allows increased physician flexibility by allowing for AV Fistula creation using the ulnar and radial veins and concomitant arteries [13] . Two catheters are inserted, initially into the brachial vein and artery. Using magnetism, the catheters are aligned and confirmed using fluoroscopy. The venous site contains the electrode which emits a burst of radiofrequency energy that introduces a connection between the arterial and venous system [14] .

Figure 1. WavelinQ AV Fistula creation using either the radial/ulnar artery and vein using magnets and radiofrequency to create a fistula.

Ellipsys:
FDA approved in 2018 [9] and one of two newly approved devices for percutaneous arteriovenous fistula creation, the Ellipsys vascular access system from Avenu Medical utilizes a novel technique in pAVF creation. Like the WavelinQ system, Ellipsys takes advantage of the proximity of the upper forearm deep communicating vein and the proximal radial or proximal ulnar arteries [15]. An alternative to WavelinQ’s magnetic and radiofrequency method, Ellipsys utilizes a combination of thermal energy and ultrasonographic guidance in the creation of pAVF. [14,16].

Figure 2. Various options for AV Fistula creation [12]

Under ultrasound guidance, access is gained to a perforating vein adjacent to the radial artery and punctured into the radial artery. A guidewire is then advanced into the radial artery followed by sheath insertion over the guidewire. The Ellipsys catheter device is then inserted. Once positioned to capture both arterial and venous walls, the Ellipsys device is activated. Simultaneously cutting and fusing adjacent arterial and venous walls using thermal energy, our AV fistula is created. Balloon angioplasty follows pAVF creation to reduce post-anastomotic stenosis [15].

Figure 3. Percutaneous AV Fistula creation using Ellipsys [7].

Impact
Since first described by Brescia and Cimino in 1966, AV fistulas have been at the cornerstone of treatment for patients with chronic renal failure. Often these fistulas serve as a lifeline for these patients. Initially, the surgical placement of an AV fistula was revolutionary and its technology not only extended the life but also the quality of patients with renal disease. However, since 1966, the surgical placement of AV fistulas has not changed much. Open surgical placement of these AV fistulas poses some initial limitations such as needing additional procedures within the preceding 12 months after procedure, slow AV fistula maturation and increased time to initial dialysis.

To further advance the technology of AV fistula placement and provide better outcomes for patients both the WavelinQ and Ellipsys systems have been developed. Both technologies provide a new means for minimally invasive placement of AV fistulas. Each of these systems uses a novel approach to create robust fistulas via minimally invasive techniques. The hope is that this technology will provide a new means to perform AV fistulas placement without the complications seen in open surgical placements. Rather than needing general anesthesia and open surgery AV fistulas can now be placed under minimal sedation and minor surgical intervention.

Recent studies done using the wavelineQ have shown promising results. A recent study comparing the wavelineQ AVFs compared to surgically placed radiocephalic AV fistulas showed that the wavelineQ AVFs showed higher rates of fistula primary patency at 400 days [17]. These results indicate that the use of the wavelineQ prolongs time from initial fistula placement to first thrombosis or any intervention needed for recanalization. For patients, this means that they will have a longer complication free interval after initial placement as compared to surgical AVF creation. These results also indicate that the use of the wavelineQ will increase the time and likelihood of fistula functionality before the need for abandonment. When comparing the WavelineQ to the Ellipsys we see similar results. A study conducted comparing the two showed that the rates of primary patency were equivalent between the two. However, it was noted that the rates of secondary patency in this study favored the Ellipsys [17]. These two single center studies suggest that these new technologies are superior to that of open surgical AF fistula placement in terms of primary and secondary patency.

Not only do both the WavelinQ and Ellipsys provide superior patency but they also provide a superior aesthetic appearance without a scar. This outcome is favorable as it improves patient satisfaction with the procedure. Further, these technologies require less postoperative follow up as no surgical incision care is needed. Finally, the increase in patency and need for intervention shown in the previous studies reduces the post fistula creation cost [18].

In conclusion the development of these two new technologies provides a novel and superior method of placement of AF fistulas. The combination of increased efficacy, reduced costs, and increased patient satisfaction make these technologies a welcome addition to the growing procedural base in interventional radiology.

References:
1. Themes UFO. Arteriovenous Fistulas. Radiologykey.com. Published June 30, 2019. Accessed April 7, 2021.

2. Bracamonte H. A brief history of dialysis. Dpcedcenter.org. Published March 10, 2016. Accessed April 7, 2021.

3. Chronic kidney disease in the United States, 2021. Cdc.gov. Published March 9, 2021. Accessed April 7, 2021.

4. Kidney disease statistics for the United States. Nih.gov. Accessed April 7, 2021.

5. Arteriovenous Fistulas. Radiologykey.com. Published June 30, 2019. Accessed April 7, 2021.

6. Mallios A, Jennings WC, Boura B, Costanzo A, Bourquelot P, Combes M. Early results of percutaneous arteriovenous fistula creation with the Ellipsys Vascular Access System. J Vasc Surg. 2018;68(4):1150-1156.

7. Arnold, Renée JG, et al. “Comparison between surgical and endovascular hemodialysis arteriovenous fistula interventions and associated costs.” Journal of Vascular and Interventional Radiology 29.11 (2018): 1558-1566.

8. Tmc.edu. Accessed April 7, 2021.
https://www.tmc.edu/news/2018/12/pumps-pipes-2018-conference-shared-greatness-of-in
novation-across-medicine-energy-and-aerospace/

9. Office of the Commissioner. FDA permits marketing of first catheter-based systems used to create vascular access for hemodialysis patients. Fda.gov. Published 2018. Accessed April 7, 2021.

10. Shahverdyan R, Beathard G, Mushtaq N, Litchfield TF, Nelson PR, Jennings WC. Comparison of Outcomes of Percutaneous Arteriovenous Fistulae Creation by Ellipsys and WavelinQ Devices. J Vasc Interv Radiol. 2020 Sep;31(9):1365-1372. doi: 10.1016/j.jvir.2020.06.008. Epub 2020 Aug 11. PMID: 32792280.

11. Hull J, Deitrick J, Groome K. Maturation for hemodialysis in the ellipsys post-market registry. J Vasc Interv Radiol. 2020;31(9):1373-1381.
12. How it works. Wavelinq.bd.com. Published December 17, 2018. Accessed April 7, 2021.
https://wavelinq.bd.com/how-it-works/

13. Inston N, Khawaja A, Tullett K, Jones R. WavelinQ created arteriovenous fistulas versus surgical radiocephalic arteriovenous fistulas? A single-centre observational study. The Journal of Vascular Access. 2020;21(5):646-651. doi:10.1177/1129729819897168

14. Avenu – Ellipsys – Avenu Medical. Avenumedical.com. Published February 17, 2016. Accessed April 7, 2021. https://avenumedical.com/ellipsys/

15. Wasse H. Place of percutaneous fistula devices in contemporary management of vascular access. Clin J Am Soc Nephrol. 2019;14(6):938-940.

16. BD receives FDA 510(k) clearance of WavelinQ 4F endoAVF system. Vascularnews.com. Published February 14, 2019. Accessed April 7, 2021.
https://vascularnews.com/bd-fda-510k-wavelinq-4f-endoavf-system/

17. R. Shahverdyan, G. Beathard, N. Mushtaq, T. F. Litchfield, P. R. Nelson, and W. C. Jennings, “Comparison of Outcomes of Percutaneous Arteriovenous Fistulae Creation by Ellipsys and WavelinQ Devices,” Journal of Vascular and Interventional Radiology, vol. 31, no. 9, pp. 1365-1372, 2020/09/01/ 2020, doi:

18. Hebibi, H., Achiche, J., Franco, G. and Rottembourg, J. (2019), Clinical hemodialysis experience with percutaneous arteriovenous fistulas created using the Ellipsys® vascular access system. Hemodialysis International, 23: 167-172.

The Leaching Problem: A Short Story about Y-90
September 25, 2021

By Jacob Poliskey & Joseph McFarland

A small village lay nestled on an island on the western side of Sweden. Carl Arrhenius, a lieutenant from the nearby city of Stockholm, was indulging his interest in gunpowder in search of new combustible elements near a mine. He noticed a most unusual band of dark, heavy metal running in the rock. This “new earth,” as he called it, was named Yttria after this small Swedish village of Ytterby.1 Little did the lieutenant know that his discovery would later serve as the foundation of one of the most fashionable and fascinating procedures in Interventional Radiology: Y-90 Radioembolization.

The liver is an incredible metabolizer of nutrients, as well as a filter of toxins, that come directly from the gut. Normal hepatic parenchyma actually receives most of its blood supply from the very gastrointestinal system that it is designed to filter. A key discovery about the liver that paved the way towards Selective Internal Radiation Therapy (SIRT) or Radioembolization, was that hepatocellular carcinomas (HCC) do not have the same dominant portal blood supply as the rest of the liver. HCC receives 80% of its blood from the hepatic artery (Figure 1).

Figure 1. Y-90 Radioembolization can successfully ablate an HCC tumor, while mostly sparing the normal hepatic parenchyma, because the HCC’s vasculature primarily comes from the hepatic artery. A catheter is guided into the supplying arteries of the tumor, and then radioactive Y-90 ceramic or glass beads are deployed at carefully dosed amounts. The beads are manufactured at such a size that they can lodge in the tumor’s capillaries without stopping blood flow. The proximity of the tumor to the lodged radioactive beads allows for selective destruction of the tumor.

Shortly after angiographers discovered the blood supply of HCC, early reports of radioembolization with Y-90 appeared. Several small studies over the 1960s-1980s demonstrated feasibility in humans, but the adverse effects outweighed the benefits of the therapy. This was often due to the toxic effects of radiation such as pneumonitis, liver disease, and gastrointestinal ulceration. Some patients even developed the most serious adverse effect of myelosuppression, attributed to yttrium leaching from the spheres and into the bone marrow. The yttrium leaching problem greatly lessened interest in and use of SIRT technology.

TheraSphere, developed in 1988, was the first technology to overcome the leaching problem. Melting aluminum oxide and silicon dioxide at 1,500°C in the presence of Y-89 forms a glass matrix with embedded non-radioactive yttrium. Neutron bombardment then transforms the Y-89 into the radioactive Y-90. As Y-90 is completely embedded within the glass, there is virtually no possibility of leakage. However, this glass-based approach came with the limitation that the glass particles were denser than blood, possibly limiting the even distribution in the tumor.1

SIR-Spheres, developed about a decade later, solved this seeping difficulty in a different way. The SIR-Spheres are composed of a cation-exchange resin. Pure radioactive Y-90 is exchanged for sodium and then precipitated with phosphate, immobilizing it within the resin. This technique leaves no room for radioactive impurities and has a theoretical benefit of better tumor distribution due to their density. To minimize Y-90 leakage, however, the SIR-Spheres were initially suspended and dosed in a non-ionic solution: pure water. This led to arterial stasis and intra-procedural pain. Subsequently, this changed to 5% dextrose in water, which helps alleviate these issues.2

Both TheraSphere and SIR-Spheres have effectively solved the leaching problem and are widely used today. There have been no trials demonstrating superiority of either method, so the platform used is simply a matter of physician or institutional preference.2

From advancements in sphere size for optimal tumor deposition to intraprocedural affirmation of tumor targeting with radio-opaque glass microspheres, this promising technology continues to forge ahead. Even now, Y-90 radioablation therapy is being explored as a curative option when historically, it has been considered only a palliative therapy3. It will be exciting to see what advances are made in the future.

Sources
1. Marshall JL, Eta B. Yttrium and Johan Gadolin. Unt.edu. Accessed November 26, 2020. http://www.chem.unt.edu/~jimm/REDISCOVERY%207-09-2018/Hexagon%20Articles/gadolin.pdf

2. Westcott MA, Coldwell DM, Liu DM, Zikria JF. The development, commercialization, and clinical context of yttrium-90 radiolabeled resin and glass microspheres. Adv Radiat Oncol. 2016;1(4):351-364.

3. What’s new in Y-90? – endovascular today. Accessed November 26, 2020. https://evtoday.com/articles/2019-oct/whats-new-in-y-90

Innovations in Uterine Fibroid Embolization
September 25, 2021

Author(s):
Matthew Henry
Wayne State University SOM ’22

Christine Lin
Pennsylvania State University SOM ’23

Vimal Gunasekaran
Medical College of Wisconsin ’22

Anushree Rai
SIR MSC Reserves Member

History
Uterine fibroids are a common occurrence in middle aged females that can cause painful and heavy menstrual bleeding.  With a prevalence of uterine fibroids estimated to be 65% in women greater than 50, successful treatment of these patients is crucial [1].  One of the growing treatment options include uterine fibroid embolization (UFE) performed by an Interventional Radiologist.

While embolizations were first described in the 1970’s for treatment of postpartum hemorrhage, vascular malformations, or devascularization of tumors, it was not until 1995 that Ravina et al. proposed embolization for treatment of uterine fibroids [2]. With 16 patients under neuroleptic analgesia, access of the right femoral artery with subsequent catheterization of the right and left uterine arteries and embolization with inert particles of Ivalon was performed until fibroid blood flow was completely interrupted. 75% of patients had a 20-80% reduction in fibroid volume and 64% of patients had symptom resolution. Additionally, in 1997 Goodwin et al. reported successful reduction of fibroid related symptoms in 88% patients treated with UFE. To date, over 40,000 UFE’s have been performed [3].

Historically, alternative treatment options for uterine fibroids include hormonal/oral contraceptive medical and surgical approaches–however, these options are not without risks. Oral contraceptive side effects include venous thromboembolism and a 20-40% increased risk of stroke. Furthermore, hormonal therapies can cause recurrence of symptoms and fibroid size after cessation. Hysterectomy is a definitive therapy of uterine fibroids and while it has the highest rate of symptom relief compared to UFE in nonrandomized controls, it carries significant major complications such as deep venous thrombosis (5%), surgical wound abscess (15%), intraabdominal abscess (5%) and transfusion (20%) [4-5].

Current Applications
Uterine fibroid embolization (UFE) is a uterus-sparing procedure performed by interventional radiologists through a transcutaneous femoral artery approach to treat symptomatic uterine fibroids [6].  Since 2008, UFE has been endorsed by the American College of Obstetricians and Gynecologists (ACOG) as a safe and effective alternative to hysterectomy to treat fibroids [7].  In this procedure, transcutaneous femoral artery approach is used to access the uterine artery, which is then embolized using embolic agents, including polyvinyl alcohol particles, trisacryl gelatin microspheres, and gelatin sponge [8]. Contraindications to this procedure include pregnancy, pelvic malignancies, and uterine or adnexal infection. Preparing for this procedure requires close collaboration among the patient, interventional radiologist, and gynecologist to assess preferences, benefits and risks [9]. As this is a minimally invasive procedure, patients often have shorter hospital stays compared to patients who undergo hysterectomies, on average by 4 days [10]. A recent single institutional study has found that same-day discharge with low rate of patient return is possible [11].

Current literature reviews of effect on fertility identify limitations in current data with small sample sizes and lack of randomization, but emphasizes that pregnancy is attainable after UFE with an approximate pregnancy rate of 38.3%, but compared to myomectomy, may have increased risk of preterm delivery and spontaneous abortion [12]. Similarly, a systematic review studying this same question found low quality of evidence and highlights the need for higher quality prospective randomized studies [13].

Patient symptom control and post-procedure satisfaction are highest in “ideal” candidates, which are women with no contraindications to UFE and with all of the characteristics like heavy regular menstrual bleeding or dysmenorrhea associated with intramural fibroids, Premenopausal and no desire for future pregnancy [14]. But the majority of women report high satisfaction with the procedure and improved quality of life. Ten year results of the randomized  Embolization vs Hysterectomy (EMMY) trial showed that close to 80% of women who received UFE were satisfied with their treatment. Eighty-one percent would suggest a friend undergo the procedure, and 74% of women who underwent UFE preferred their treatment modality compared to hysterectomy [15]. Several other studies also report sustained improvement in symptom severity and overall quality of life. [16, 17].

After UFE, patients can reasonably expect resolution of symptoms such as menorrhagia (90 – 92% of patients), pelvic pressure, and pelvic pain (88 – 96% of patients). Although infrequent, major adverse events can occur and include ovarian failure and future amenorrhea (7.5% of patients in FIBROID Registry), fibroid expulsion, and rarely venous thromboembolism with possible pulmonary embolism[18]. However, at one year post-embolization, UFE significantly improves all aspects of sexual function measured by Female Sexual Function Index (FSFI) and quality of life [19].

UFE is generally safe in patients with symptomatic fibroids. Obese patients (BMI > 30) and those with large volume uteri (> 1000cm3) are at slight increased risk of developing infection and require appropriate pre-procedural counselling, as well as careful post-UFE follow-up. BMI and uterine volume may be useful to assess before the procedure to help to determine post-UFE infection risk [20].

Impact and Future Directions
While uterine artery embolization (UAE) has demonstrated short term advantages, such as shorter and less painful recovery compared to surgery, the long-term outcomes are not as clear. The 10-year results of the EMMY trial, which was a randomized controlled trial of UAE versus hysterectomy for the treatment of symptomatic leiomyomas, showed that 31% of patients who received successful UAE underwent secondary hysterectomy [21]. Similarly, a meta-analysis examining UAE compared to surgical procedures for the treatment of symptomatic leiomyomas reported increased risk of re-intervention in the UAE group after both two and five years [22]. Incomplete infarction of the leiomyoma, which subsequently results in the growth of the non-infarcted tissue, may lead to symptom recurrence and the indication for additional intervention [23].

Future innovations of UAE are looking to address the current inadequacies of the treatment modality. For example, a recent study explored the use of a convolutional neural network (ResNet) model to predict UAE outcomes using routine magnetic resonance imaging [24]. ResNet is a deep learning model that learns hierarchical representations of imaging data. Using T1-weight contrast-enhanced (T1C) sequence images, the model demonstrated a better test accuracy, sensitivity, and specificity than four radiologists. Similar to other machine learning technologies, this model is unlikely to replace radiologists. Instead, it is likely that in the not-so-distant future that both diagnostic and interventional radiologists will use machine learning models to aid in the selection of patients that are most likely to benefit from UAE.

In addition to utilization of imaging models to improve clinical outcomes of UAE, the continued advancement of embolic materials deployed in UAE will likely also improve patient outcomes. A recent randomized controlled trial published by Han et al. investigated pain following UAE for symptomatic leiomyomas with either non-spherical polyvinyl alcohol particles (PVA) or tris-acryl microspheres (TAGM) [25]. Although patients who received PVA and TAGM showed equivalent pain scores and fentanyl dose, the two groups were not completely equivalent. The authors concluded that the utilization of PAV led to a greater inflammatory response and subsequently higher analgesic use, and more frequent transient global uterine ischemia.

Uterine artery embolization has significantly advanced the treatment of uterine fibroids. Nonetheless, there are still advances to be made. Additional research in all aspects of UAE will result in identification of variables that interventional radiologists can address in order to improve clinical outcomes.

References:
1. Ghant MS, Sengoba KS, Recht H, Cameron KA, Lawson AK, Marsh EE. Beyond the physical: a qualitative assessment of the burden of symptomatic uterine fibroids on women’s emotional and psychosocial health. J Psychosom Res. 2015 May;78(5):499-503. doi: 10.1016/j.jpsychores.2014.12.016. Epub 2015 Feb 2. PMID: 25725565.

2. Ravina JH, Herbreteau D, Ciraru-Vigneron N, Bouret JM, Houdart E, Aymard A, Merland JJ. Arterial embolisation to treat uterine myomata. Lancet. 1995 Sep 9;346(8976):671-2. doi: 10.1016/s0140-6736(95)92282-2. PMID: 7544859

3. Raikhlin A, Baerlocher MO, Asch MR. Uterine fibroid embolization: CME update for family physicians. Can Fam Physician. 2007;53(2):250-256.

4. Silberzweig JE, Powell DK, Matsumoto AH, Spies JB. Management of Uterine Fibroids: A Focus on Uterine-sparing Interventional Techniques. Radiology. 2016 Sep;280(3):675-92. doi: 10.1148/radiol.2016141693. PMID: 27533290.

5. Pinto I, Chimeno P, Romo A, Paúl L, Haya J, de la Cal MA, Bajo J. Uterine fibroids: uterine artery embolization versus abdominal hysterectomy for treatment–a prospective, randomized, and controlled clinical trial. Radiology. 2003 Feb;226(2):425-31. doi: 10.1148/radiol.2262011716. PMID: 12563136.

6. Ravina JH, Ciraru-Vigneron N, Bouret JM, et al. Arterial embolisation to treat uterine myomata. The Lancet. 1995;346(8976):671-672. doi:10.5555/uri:pii:S0140673695922822

7. ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of Leiomyomas. Obstet Gynecol. 2008;112(2 Part 1):387-400. doi:10.1097/AOG.0b013e318183fbab

8. Goodwin SC, Spies JB. Uterine Fibroid Embolization. doi:10.1056/NEJMct0806942

9. Bulman JC, Ascher SM, Spies JB. Current Concepts in Uterine Fibroid Embolization. RadioGraphics. 2012;32(6):1735-1750. doi:10.1148/rg.326125514

10. Silberzweig JE, Powell DK, Matsumoto AH, Spies JB. Management of Uterine Fibroids: A Focus on Uterine-sparing Interventional Techniques. Radiology. 2016;280(3):675-692. doi:10.1148/radiol.2016141693

11. Sher A, Garvey A, Kamat S, et al. Single-System Experience With Outpatient Transradial Uterine Artery Embolization: Safety, Feasibility, Outcomes, and Early Rates of Return. AJR Am J Roentgenol. Published online February 3, 2021:1-6. doi:10.2214/AJR.20.23343

12. Ludwig PE, Huff TJ, Shanahan MM, Stavas JM. Pregnancy success and outcomes after uterine fibroid embolization: updated review of published literature. Br J Radiol. 2019;93(1105):20190551. doi:10.1259/bjr.20190551

13. Karlsen K, Hrobjartsson A, Korsholm M, Mogensen O, Humaidan P, Ravn P. Fertility after uterine artery embolization of fibroids: a systematic review. Arch Gynecol Obstet. 2018;297(1):13-25. doi:10.1007/s00404-017-4566-7

14. Young M, Coffey W, Mikhail LN. Uterine Fibroid Embolization. 2020 Jul 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 30085558.

15. de Bruijn, A. M., Ankum, W. M., Reekers, J. A., Birnie, E., van der Kooij, S. M., Volkers, N. A., & Hehenkamp, W. J. (2016). Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 10-year outcomes from the randomized EMMY trial. American journal of obstetrics and gynecology, 215(6), 745-e1.

16. Goodwin, S. C., Spies, J. B., Worthington-Kirsch, R., Peterson, E., Pron, G., Li, S., & Myers, E. R. (2008). Uterine artery embolization for treatment of leiomyomata: long-term outcomes from the FIBROID Registry. Obstetrics & Gynecology, 111(1), 22-33.

17. Smith, W. J., Upton, E., Shuster, E. J., Klein, A. J., & Schwartz, M. L. (2004). Patient satisfaction and disease specific quality of life after uterine artery embolization. American journal of obstetrics and gynecology, 190(6), 1697-1703.

18. Bulman JC, Ascher SM, Spies JB. Current concepts in uterine fibroid embolization. Radiographics. 2012 Oct;32(6):1735-50. doi: 10.1148/rg.326125514. PMID: 23065167.

19. Kovacsik HV, Herbreteau D, Bommart S, Beregi JP, Bartoli JM, Sapoval M; French Society of Interventional and cardiovascular Imaging (SFICV) research group. Evaluation of Changes in Sexual Function Related to Uterine Fibroid Embolization (UFE): Results of the EFUZEN Study. Cardiovasc Intervent Radiol. 2017 Aug;40(8):1169-1175. doi: 10.1007/s00270-017-1615-3. Epub 2017 Mar 20. PMID: 28321542.

20. Mollier J, Patel NR, Amoah A, Hamady M, Quinn SD. Clinical, Imaging and Procedural Risk Factors for Intrauterine Infective Complications After Uterine Fibroid Embolisation: A Retrospective Case Control Study. Cardiovasc Intervent Radiol. 2020 Dec;43(12):1910-1917. doi: 10.1007/s00270-020-02622-2. Epub 2020 Aug 26. PMID: 32851424; PMCID: PMC7649153.

21. de Bruijn, A. M., Ankum, W. M., Reekers, J. A., Birnie, E., van der Kooij, S. M., Volkers, N. A., & Hehenkamp, W. J. (2016). Uterine artery embolization vs hysterectomy in the treatment of symptomatic uterine fibroids: 10-year outcomes from the randomized EMMY trial. American journal of obstetrics and gynecology, 215(6), 745-e1.

22. Fonseca, M. C., Castro, R., Machado, M., Conte, T., & Girao, M. J. (2017). Uterine artery embolization and surgical methods for the treatment of symptomatic uterine leiomyomas: a systemic review and meta-analysis followed by indirect treatment comparison. Clinical therapeutics, 39(7), 1438-1455.

23. Pelage, J. P., Guaou, N. G., Jha, R. C., Ascher, S. M., & Spies, J. B. (2004). Uterine fibroid tumors: long-term MR imaging outcome after embolization. Radiology, 230(3), 803-809.

24. Luo, Y. H., Xi, I. L., Wang, R., Abdallah, H. O., Wu, J., Vance, A. Z., … & Shlansky-Goldberg, R. (2020). Deep learning based on mr imaging for predicting outcome of uterine fibroid embolization. Journal of Vascular and Interventional Radiology, 31(6), 1010-1017.

25. Han, K., Kim, S. Y., Kim, H. J., Kwon, J. H., Kim, G. M., Lee, J., … & Kim, M. D. (2020). Nonspherical Polyvinyl Alcohol Particles versus Tris-Acryl Microspheres: Randomized Controlled Trial Comparing Pain after Uterine Artery Embolization for Symptomatic Fibroids. Radiology, 201895.

Challenging the Zeitgeist of Stereotactic Surgical Oncology: The Past, Present, and Future of Percutaneous Tumor Ablation Therapy
September 25, 2021

Author(s):
Sherayar Orakzai
Medical College of Georgia ’21

Ivan Dimov
University of Montreal School of Medicine ’23

Devin DeLuna
University of Nebraska Medical Center ’22

Editor(s):
Yang (John) Qiao, M.D.
PGY-2 Integrated Interventional and Diagnostic Radiology
University of Texas Health Science Center at Houston / M.D. Anderson Cancer Center

Introduction
As cross-sectional imaging became widely available in the 1970s, so did the ability to precisely-target visceral tumors in a percutaneous approach with ablative therapies.  Percutaneous ablation is a modern-day technique in oncological care which utilizes thermal or cryogenic modalities for in situ destruction of solid tumors via induction of cellular injury, ultimately leading to tumor apoptosis, necrosis, and death.  Although historically utilized when disease stage, tumor location, and/or poor patient fitness status preclude the option of surgical resection or whole organ transplantation, the choice of percutaneous ablation over surgical resection is continuously gaining ground as an equal stereotactic method when a number of factors are taken into account including tumor type, size, organ, number of tumors, and the technology available to the operator.  Today, evidence-based treatment algorithms support its use by Interventional Radiologists for a wide-array of tumor etiologies including hepatocellular carcinoma, liver metastasis, non-small cell lung cancer, and renal cell carcinoma.  In general, tumors are ablated using 3 temperature-based techniques: radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. These modalities use percutaneous probes inserted within the tumor that heat up to temperatures above 55 C in case of RFA and MWA, or freeze below -20 to -35 C in cryoablation, which results in cell death.  This article will focus on the historical developments of these three predominant ablation modalities; address the technical aspects, challenges, and limitations of percutaneous ablation modalities in a variety of organ- and tissue-specific cancers; and provide future outlook on percutaneous ablation therapies, as well as an introduction to combination ablation therapies, and the investigational next-generation modality of percutaneous electroporation therapy.

The Development of Percutaneous Ablation Therapies- How it Happened
Although the first clinically-documented RFA for percutaneous cancer treatment was performed in 1988 within the liver, the basic technique of utilizing radiofrequency currents as a general thermogenic clinical treatment modality was first investigated over a century ago by the French Physician Jacques-Arsène d’Arsonval using high frequency electrical currents (10,000 cycles per second) in animal models.1 This technique became known as “darsonvalization” and was mostly used to remove cutaneous and mucous membrane growths.  Later on in the 1930s, American Physician Edwin Beer pioneered the ability of applying direct targeted radiofrequency waves via cystoscopy for removing urologic papillary tumors. As advanced research led to better understanding of differential organ-specific conductivities and the relationship between wavelength and heat generation, the precision of RFA therapy became further calibrated for percutaneous ablation of organ-specific malignancies.  Recent advancements, including internal electrode cooling and multi-electrode application are constantly fine-tuning its clinical efficacy.

The more recently developed percutaneous thermal ablation modality of microwave ablation (MWA) was initially studied in Japan and China in the early 2000s.2 MWA utilizes a process of dielectric hysteresis (rotating dipoles) for generating heat within an aqueous environment. The rotation of dipoles within an applied electromagnetic field generates kinetic energy, which is transferred to adjacent local tissue in the form of ablation-grade heat energy. Despite its recent emergence as an accepted percutaneous cancer ablation modality, MWA has undergone rapid advancements, notably in active antenna cooling and high-power generation technologies.

Unlike thermal ablation, cryoablation utilizes the application of subzero temperatures to facilitate local tumor destruction. Observational damage of frost-bite was first empirically-tested as a therapeutic agent in the 1800s by English Physician James Arnott.3 Using a mixed salt and ice solution, Arnott designed an apparatus for applying frost as a localized therapeutic agent for treating cancers of the breast and female cervix, demonstrating pain palliation and a decrease in overall tumor size.  Subsequently, the term “cryogen” was coined.  Shortly after in 1889, cryogens made from various liquified gasses (including oxygen, nitrogen, and hydrogen) and applied via spray or brass roller devices became used for the treatment of various skin lesions, including epitheliomas.  In 1960, modern percutaneous solid organ cryoablation became feasible with advances in trocar-based cryogenic delivery systems.4 With the initiation of cryogenic therapy using nitrogen-cooled probes for neurovascular cryosurgery of the basal ganglia in Parkinson Disease patients, cryosurgery began rapidly evolving into an inclusive modality for the treatment of various localized cancers in breast, brain, prostate, kidney, and bone lesions.3 Recent advancements include argon-based cryogen generation technologies, and the role of intraoperative ultrasound in monitoring real-time tissue cryogenesis.

Organ-Specific Applications- Choosing the Appropriate Percutaneous Ablation Modality
Tumor ablation in the liver is typically performed for hepatocellular carcinoma (HCC) and metastatic disease, but can also be used to treat benign tumors such as hemangiomas and adenomas.5 HCC is staged using the Barcelona Clinic Liver Cancer (BCLC) scale, with ablation offered in early stage disease (stage 0 or A), with curative intent equal to tumor resection or transplantation.6 In these tumors, heat-based ablation is typically preferred as it avoids the complications related to cryotherapy, including the risk for hemorrhage and cryo-shock (a term used to describe a reaction similar to disseminated intravascular coagulation caused by the release of cellular debris following cryoablation).7 Another difficulty with cryoablation is predicting coverage of tumor margins, since tissues can remain viable at the margins of the iceball where temperatures are not below -20 to -35 C. In general, RFA is used for HCC 2-3 cm in diameter, and MWA is preferred for larger tumors, multiple tumors, and for tumors located within liver parenchyma near neighboring larger vessels.5 since MWA is less susceptible to the heat-sink effect (a phenomenon in which blood flow from neighboring vessels draws out heat from the adjacent ablation zone and thereby decreases the ablative efficacy).2 However, cryoablation can sometimes be considered when treatment of lesions near important hilar structures requires close monitoring of the ablation zone, as cryogenesis allows for a more graduated control of ablation margins.

Although the current preferred treatment modality for renal cell carcinoma is partial nephrectomy, patients who are poor surgical candidates (such as those with compromised kidney function and poor fitness status) can benefit from percutaneous ablative therapy.8 Due to the kidneys’ relatively small size and proximity to other important retroperitoneal and abdominal organs, ablation in this region requires careful targeting with cross sectional imaging and the use of hydrodissection (a technique in which saline is injected adjacent to the kidney, separating it from adjacent organs such as bowel to prevent iatrogenic injury during ablation). To protect against iatrogenic collecting system damage, warm saline is sometimes preoperatively infused retrograde through the ureters, via a technique called pyeloperfusion.8 Apart from renal cell carcinoma, benign tumors such as angiomyolipoma and oncocytoma have been treated with all three modalities. Due to its greater precision and slower action of onset, cryoablation is advantageous for the treatment of larger tumors and of tumors closer to the renal pelvis. In fact, recent retrospective studies have demonstrated favorable oncologic outcomes and decreased perioperative complications of cryoablation for treating stage T1a renal cell carcinoma compared with partial nephrectomy.9 RFA is also utilized, although it is empirically less effective for targeting angioliposarcomas, where adipose tissue increases electrical impedance. MWA is preferred for exophytic tumors surrounded by a safety margin of capsular fat.

Ablation of primary and metastatic tumors in the lung presents technical challenges for all three modalities. Since RFA has produced mixed results due to the inherent impedance of air in lung tissue (which hampers the effective formation of an ablation zone), MWA is therefore the ablation-of-choice for most lung lesions due to its rapid and efficient heat production.2  For lesions closer to the chest wall or mediastinum, cryoablation is used as it is less painful and better tolerated by nerve fibers in the adjacent chest wall.

Soft tissue and bone tumors can also be effectively treated with percutaneous ablation. As an alternative to radiation therapy, both thermal and cryogenic techniques are used to treat metastatic tumors within bone, which causes prolonged and treatment-resistant pain for many patients with advanced malignancy. Cryoablation is empirically the preferred modality for effective pain management and relief for bone metastases.8 Additionally, percutaneous ablation is now also the preferred treatment for osteoid osteoma, a benign but painful tumor most often found in the long bones of children and young adults.  Here, RFA delivers an excellent cure rate with minimal treatment related morbidity, as opposed to conventional surgical curettage.

The Future of Percutaneous Ablation Therapies – Where it’s Going
The outlook for the future growth and development of percutaneous tumor ablation is positive. Recent market research estimates the global market for tumor ablation will expand from 646.4 million USD in 2020, to 2.4 billion USD in 2028. This projection is attributed to the increasing incidence of cancer from an aging population, and the benefits of minimally invasive procedures such as shorter hospital stays and greater patient comfort.10 Although conventional techniques of tumor ablation have their limitations, these same limitations will reciprocally spur innovation for further development of more effective ablation modalities.

Progress is quickly being advanced in the realm of combination ablation therapies, in which concurrent application of local therapies augment the effect of tumor ablation.  Transarterial chemoembolization in combination with radiofrequency or microwave ablation is a well-established example of combination ablation therapy.  Of particular interest is the combination of ablation with immunotherapy. Tumor ablation, and in particular cryoablation, has demonstrated an ability to generate a systemic postablative anti-tumor response against exposed tumor poly-antigens following in situ ablation, which is largely not seen following surgical resection.  A study performed utilizing murine models of mammary adenocarcinoma demonstrated resistance to growth against re-implanted mammary cancer cells in 84% of mice that underwent cryoablation of the initial in situ tumor, providing empirical evidence of long-term potentiation and the generation of an adaptive tumor-specific immune response from cryoablation. Comparatively, only 14% of mice that underwent surgical resection resisted tumor growth following re-implantation of the mammary adenocarcinoma cell line. A wide variety of immunologic targets are now under investigation for their post-ablative tumor response-enhancing potential, including CpG-oligodeoxynucleotides (Toll-Like receptor [TLR] 9 agonist), imiquimod (TLR7 agonist), anti-CD25 antibodies, and anti-PD-1 antibodies.  Each of these therapies have so far demonstrated promising effects on survival following tumor ablation, and champion the importance of continued research into the synergistic effects and identification of future combination ablation therapies.11

New ablation modalities are also on the horizon for the interventional oncologist. Although thermal energy is currently most widely used for oncologic tissue ablation, limitations from the heat sink effect for targeting lesions near large vessels have driven innovation towards forms of non-thermal ablation, such as the relatively novel irreversible electroporation (IRE).  Although the technology behind electroporation has been utilized since the 1980s for genetics and chemotherapy applications, it wasn’t until the early 2000s that IRE was studied for tissue ablation. IRE is a non-thermal ablation modality that utilizes electrical pulses to disrupt the cellular membrane integrity by puncturing hydrophilic holes within the lipid bilayer of tumor cells, which disrupts voltage-gated protein channels, and ultimately leads to a loss cellular homeostasis resulting in cell death.12  Although IRE has been shown to create some thermal energy sufficient to induce thermal coagulation in specific settings, the primary mechanism-of-action for inducing cellular apoptosis via IRE is still non-thermal.13  Freedom from the thermal heat sink effect positions IRE as a potential modality-of-choice for treating tumors in close proximity to larger vessels (such as HCC located near large hepatic or portal veins) without losing ablative efficacy.14  Additionally, cellular proteins and surrounding microvasculature within the electrolytic ablation zone is spared with IRE, which preserves tumor damage-associated molecular pattern molecules for enhancing immunogenic anti-tumor T-cell responses in the post-ablative tumor bed.15  Overall, these features of IRE could potentially expand the indications for percutaneous tumor ablation. The future of IR will likely involve integration of IRE as this modality is further studied and refined.

Lastly, future advances in new imaging and guidance technology will be crucial in facilitating and expanding the scope of tumor ablation for the Interventional Radiologist. Percutaneous tumor ablation can be hindered by the need for frequent adjustments in needle positioning within tumors situated in difficult anatomy.16 One of the most recent and significant advances in interventional radiology comes from the introduction of cone beam CT, an imaging modality which allows for intraoperative evaluation of a target-of-interest with reconstructive 3D volumetric imaging. Cone beam CT has vastly improved targeting of tumors intraoperatively, which previously depended on 2D digital subtraction angiography for localization.17 Further development of fusion imaging such as real-time US/CT-MR imaging is also enhancing visualization of tumors that would have otherwise been inconspicuous using conventional B-mode US.18 Looking further into the future, augmented-reality (AR) technology may be the next imaging modality that becomes incorporated into the IR suite. Although this technology is still being refined, it is easy to imagine how AR could provide pragmatic assistance in the IR suite from displaying 3D needle trajectories to visualizing tumor ablation margins.19 Clinical trials are currently underway for investigating the feasibility of AR for peri-operative planning and assistance in percutaneous liver ablation.20

References:
1. Anthony C. Venbrux, F. R., Ellen C. McCormick, Christopher Lawrence, Chapman Wei, Liqi Shu, Yuanlong Zhao, Rabia Idrees, Uzomo Igboagi, Andrew Nelson, Anam Salman. Image-Guided Interventions. Elsevier; 2020.

2. Ahmed M, Brace CL, Lee FT Jr, Goldberg SN. Principles of and advances in percutaneous ablation. Radiology. 2011 Feb;258(2):351-69. doi: 10.1148/radiol.10081634. PMID: 21273519; PMCID: PMC6939957.

3. Ahmed M, Brace CL, Lee FT Jr, Goldberg SN. Principles of and advances in percutaneous ablation. Radiology. 2011 Feb;258(2):351-69. doi: 10.1148/radiol.10081634. PMID: 21273519; PMCID: PMC6939957.

4. Cooper SM, Dawber RP. The history of cryosurgery. J R Soc Med. 2001;94(4):196-201. doi:10.1177/014107680109400416

5. Ton J, Kuoy E, Abi-Jaoudeh N. Liver Ablation. In: IR Playbook. Springer International Publishing; 2018:397-403. doi:10.1007/978-3-319-71300-7_36

6. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-1255. doi:10.1016/s0140-6736(11)61347-0

7. Louis Hinshaw J, Lubner MG, Ziemlewicz TJ, Lee FT, Brace CL. Percutaneous tumor ablation tools: Microwave, radiofrequency, or cryoablation-what should you use and why? Radiographics. 2014;34(5):1344-1362. doi:10.1148/rg.345140054

8. Mauro DM. Lung, Kidney, and Bone Ablation. In: IR Playbook. Springer International Publishing; 2018:405-415. doi:10.1007/978-3-319-71300-7_37

9. Haddad MM, Schmit GD, Kurup AN, et al. Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes. J Vasc Interv Radiol. 2018;29(8):1122-1126. doi:10.1016/j.jvir.2018.02.029

10. Tumor ablation market size worth $2.4 billion by 2028 | CAGR: 13/2%: Grand view research, inc. https://markets.businessinsider.com/news/stocks/tumor-ablation-market-size-worth-2-4-billion-by-2028-cagr-13-2-grand-view-research-inc-1030042447. Published February 04, 2021. Accessed February 13, 2021

11. Slovak R, Ludwig JM, Gettinger SN, Herbst RS, Kim HS. Immuno-thermal ablations – boosting the anticancer immune response. J Immunother Cancer. 2017;5(1):78. Doi: 10.1186/s40425-017-0284-8

12. Geboers B, Scheffer HJ, Graybill PM, et al. High-voltage electrical pulses in oncology: Irreversible electroporation, electrochemotherapy, gene electrotransfer, electrofusion, and electroimmunotherapy. Radiology. 2020;295(2):254-272. https://doi.org/10.1148/radiol.2020192190. doi: 10.1148/radiol.2020192190.

13. Faroja M, Ahmed M, Appelbaum L, et al. Irreversible electroporation ablation: Is all the damage nonthermal? Radiology. 2013;266(2):462-470. https://doi.org/10.1148/radiol.12120609. doi: 10.1148/radiol.12120609.

14. Distelmaier M, Barabasch A, Heil P, et al. Midterm safety and efficacy of irreversible electroporation of malignant liver tumors located close to major portal or hepatic veins. Radiology. 2017;285(3):1023-1031. doi: 10.1148/radiol.2017161561.

15. Bulvik BE, Rozenblum N, Gourevich S, et al. Irreversible electroporation versus radiofrequency ablation: A comparison of local and systemic effects in a small-animal model. Radiology. 2016;280(2):413-424. doi: 10.1148/radiol.2015151166.

16. Abdullah, BJJ, Yeong CH, Goh KL, et al. Robotic-assisted thermal ablation of liver tumours. Eur Radiol 25, 246–257 (2015). doi:10.1007/s00330-014-3391-7

17. Degrauwe N, Hocquelet A, Digklia A, Schaefer N, Denys A, Duran R. Theranostics in interventional oncology: Verstile carriers for diagnosis and targeted image-guided minimally invasive procedures. Frontiers in Pharmacology. 2019;10:450. doi:10.3389/fphar.2019.00450

18. Ahn SJ, Lee JM, Lee DH, et al. Real-time US-CT/MR fusion imaging for percutaneous radiofrequency ablation of hepatocellular carcinoma. J Hepatol. 2017;66(2):347-354. doi:10.1016/j.jhep.2016.09.003

19. Park BJ, Hunt SJ, Martin C, Nadolski GJ, Wood BJ, Gade TP. Augmented and mixed reality: Technologies for enhancing the future of IR. Journal of Vascular and Interventional Radiology. 2020;31(7):1074-1082. doi: 10.1016/j.jvir.2019.09.020

20. Study demonstrates the feasibility of hologram technology in liver tumor ablation. https://www.sirweb.org/media-and-pubs/media/news-release-archive/sir-2020-augmented-reality-061520/. Published June 14, 2020. Accessed February 13, 2021

Innovations in Prostatic Artery Embolization
September 25, 2021

Author(s):
Jonathan Wakim
Perelman School of Medicine ’23

Triet Do
Tulane School of Medicine ’22

Caitlin Smith
Touro School of Medicine ’24

Pascal Acree
Medical College of Georgia ’24

Akshita Pillai
UTMB School of Medicine ’22

History
Benign prostatic hyperplasia (BPH) is a common condition in men over the age of 60 that can cause symptoms such as urinary urgency, nocturia, decreased urinary flow rates, hesitancy, and incomplete bladder emptying. Effective treatment of BPH is important in order to improve quality of life and prevent complications such as bladder stones, urinary tract infections, and damage to the bladder. Recently, prostatic artery embolization (PAE) performed by an interventional radiologist has been approved as a safe, minimally invasive treatment option to alleviate symptoms secondary to BPH.1

Transcatheter arterial embolization for urologic disease was first reported in 1976 by Mitchell et al for managing severe hematuria due to uncontrollable bleeding from the bladder or prostate when all other measures were unsuccessful.2 This technique involved embolization of bilateral internal iliac arteries to treat the life-threatening bleeding. This technique has since evolved to more selective catheterizations of specific internal iliac branch arteries with the development of microcatheters. The benefit of PAE was first discovered in 2000 by DeMeritt et al when the authors embolized the right inferior vesical artery until complete devascularization of the prostate. This resulted in a reduction of prostate volume by 40% and a decrease in the patient’s urinary tract symptoms.3 In 2015 de Assis et al treated 35 patients with BPH using PAE and observed a significant reduction in urinary tract symptoms and prostate volume with no major complications reported.4

Currently, moderate to severe symptoms resulting from BPH are commonly treated either pharmacologically, or with prostate surgery. Pharmacologic therapy commonly includes α-adrenergic blockers, 5α-reductase inhibitors, or muscarinic receptor antagonists.1 These drugs are effective but can be associated with many side effects including dry mouth, blurred vision, tachycardia, urinary retention, constipation, erectile dysfunction and delirium.5 Transurethral resection of the prostate (TURP) is regarded as the surgical gold standard for BPH, however this procedure may result in complications including acute urinary retention, retrograde ejaculation, urinary tract infection, bladder neck stenosis, erectile dysfunction, and bleeding.1 In contrast to surgical treatments, PAE has the advantages of being a minimally invasive, outpatient procedure with a low risk of major complications and shorter recovery time. Current data is very promising for PAE, but further studies are required before it becomes a part of standard-care-treatment for BPH.

Current Indications
PAE is a minimally invasive treatment option for men with symptomatic BPH. Constriction of the urethra due to BPH can cause symptoms including bladder obstruction and lower urinary tract problems (frequency, urgency, nocturia, weak urinary stream, urinary tract infections and bladder stone disease). A pre-procedural workup is required for patients undergoing PAE. This includes measuring baseline prostate specific antigen (PSA) and a full urologic clinical evaluation. Patients complete questionnaires to quantify their baseline urinary and erectile function.Urodynamic testing is done to evaluate the extent of bladder obstruction, the maximum urinary stream and the contractile capability of the bladder. Prostate biopsy or imaging studies with CT/MRI can be obtained based on a case-by-case basis⁶.

PAE is a procedure in which embosphere particles are used to occlude the prostatic artery. The prostatic artery usually arises from the anterior division of the internal iliac artery. However, prostatic artery size and origin differs among patients and even between the right and left side of an individual.. Furthermore collateral vessels from adjacent pelvic organs can anastomose with the prostatic artery, or extraprostatic vessel supply may also be present⁶. Thus, knowledge of the patient’s vascular anatomy is important in identifying the prostatic artery as well as preventing non-target embolization. Intraprocedural cone beam CT (CBCT) is used in conjunction with digital subtraction angiography (DSA) to target both prostatic arteries and to identify accessory or collateral supplies⁶. Embolization of PAE is pressure-dependent due to the small arterial caliber. High injection pressures can increase likelihood of reflux and nontarget embolization. Therefore, slow controlled embolization with diluted particles is performed⁶.

Due to contrast use, poor renal function can be an excluding factor for PAE determination. Atherosclerotic or tortuous vessels of the prostate are also contraindications.  Patients with previous pelvic radiotherapy, bladder calculi, or diverticulae are also not suitable for PAE.7 The need for prostatic biopsy is not addressed with PAE and requires an additional procedure.

Acute urinary retention occurs in roughly one-fourth to a third of patients following PAE. Post-PAE syndrome is the most common complication occurring in ~9% of patients and includes perineal pain, nausea/vomiting, and dysuria. Puncture site hematomas are of low incidence (<1%) and this risk is much less than that of trans-urethral resection of the prostate (TURP).7 Prophylactic antibiotics are administered to decrease the incidence of urinary tract infection following PAE.

Future Directions
TURP is currently considered the standard surgical treatment for BPH and generally results in immediate improvement of bladder obstruction. However, TURP can cause lifestyle-limiting side effects such as urinary stricture, retrograde ejaculation and erectile dysfunction. Additionally, TURP requires significant operative time and hospitalizationFor these reasons, PAE has emerged as an attractive option due to its endovascular approach with a beneficial side effect profile. Current evidence demonstrates that PAE maintains sexual function and ejaculation, but is shown to be less effective in terms of functional outcomes such as maximum urinary flow, post void residual, and reduction of prostate volume.8 However, it should be noted that some of these outcomes, especially differences in quantified urodynamics, are of questionable clinical relevance. Furthermore, although relief of obstruction has been shown to be inferior to TURP in comparative studies, PAE has advantages over TURP in treating patients on anticoagulation or large glands (over 100 cc).9 There are significantly fewer adverse events occurring in patients undergoing PAE versus TURP, namely hematuria, UTI, irritative voiding symptoms, and urethral strictures. PAE has also been shown in cost analyses to be associated with significantly lower direct in-hospital costs and shorter hospital stay. Disadvantages of PAE include longer time for symptom relief, need for ionizing radiation and iodinated contrast, and the rare events of non-target embolization causing, for example, rectal or bladder ischemia. Current research is investigating the effectiveness of PAE using different materials such as HydroPearl beads versus medication for treatment of BPH, exploring ways to reduce the postembolization syndrome in men undergoing PAE, and evaluating PAE for treatment of BPH in larger prostate glands. More high-quality studies such as well-designed randomized controlled trials and meta-analyses of randomized controlled trials are necessary to definitively evaluate and compare efficacy of treatment for BPH. Furthermore, larger-scale studies and longer follow-up periods are necessary to explore long-term effects of this intervention, as well as define the indication for PAE in treatment of BPH.

Current applications have focused on utilizing PAE for treatment of BPH; however PAE is also being considered for intractable prostatic bleeding, similar to management of splenic rupture, epistaxis, or postpartum hemorrhage. Refractory bleeding often occurs in the setting of prostate cancer or post-operative or traumatic bleeding. Current studies show success in control of bleeding, with minor complications ranging from 10-50% and recurrence of hematuria ranging from 10-57%. Though most of the data has been retrospective, heterogenous, or studied in case series, the procedure currently appears safe with low risk of complications and accomplishes technical and clinical success, especially in patients who are poor candidates for surgical intervention.10,11

The true paradigm shift lies in the successful development of a transarterial embolization procedure capable of directly treating prostate cancer (PCa). Such a procedure would need to be technically feasible, safe, and effective at palliating or treating some subset of prostate cancer patients. Pisco et al have demonstrated in a single-center prospective cohort study that prostatic artery chemoembolization (PAC) may be a viable management option for men with prostate cancer. Although the study sample size is small with only 20 patients, the authors show that both safety and periprocedure morbidity are acceptable. In addition, most treated patients experienced a biochemical response and a trend toward improved quality of life.12

Assuming future studies can demonstrate a benefit in delaying PCa progression, men with localized disease and weary of active surveillance can choose prostate cancer chemoembolization as an initial option and not exclude curative therapy (eg, surgery or radiation) at a later date. Through choosing PAC initially, the side effects of definitive treatment (eg. urinary incontinence, erectile dysfunction, radiation effects to bladder and rectum) are diminished or possibly never experienced. In patients with locally advanced disease, PAC may delay the need for androgen deprivation therapy and consequently the side effects associated with castrate levels of testosterone (eg, fatigue, hot flashes, depression, changes in body composition, cardiovascular decline). Finally, in men with locally advanced or metastatic disease (especially men with castrate-resistant PCa), PAC can control the local symptoms of advanced cancer (eg, gross hematuria, lower urinary tract symptoms, bladder outlet obstruction, ureteral obstruction and hydronephrosis) and drastically improve a patient’s quality of life from a palliative perspective.13 However, larger prospective studies are needed to demonstrate the utility of PAC in PCa management and, specifically, to identify men most likely to benefit. More importantly, the effect and potential risks based on disease stage need to be ascertained. Only then can PAC become a recognized management option for men with PCa.

Another recent development with potentially significant future implications is intra-arterial delivery of Y-90 microspheres to deliver high-dose radiotherapy to prostatic tissue to treat locally advanced prostate cancer. Led by Dr. Sam Mouli of Northwestern University, a team of researchers utilized an animal model previously used to establish the basis of PAE and safety for BPH treatment. The team looked to show technical delivery and safety of Y-90 microbeads to prostatic tissue. The team delivered escalated doses of Y-90 microspheres and looked at any postoperative complications in the subsequent three months. Imaging follow-up demonstrated prostate reduction in a dose-dependent fashion starting at two weeks post-embolization and continuing to three months post-therapy, when compared to the untreated contralateral side. The investigators report no clinical adverse events or evidence of nontarget embolization or of any radiation damage to the surrounding bladder, rectum, and erectile tissues on MRI and pathologic analysis. The team is hoping to push this promising work into a clinical trial to bring Y-90 as a potential treatment modality to patients with BPH.14

Alternatives to transarterial embolotherapy for prostate cancer and BPH include transperineal or transrectal thermal ablative techniques, such as cryotherapy, laser therapy, high-intensity focused ultrasound (HIFU), steam ablation (REZUM), and mechanical BPH decompression (UroLift). These techniques provide similar results to PAE and are generally shorter outpatient procedures accomplished without radiation (guided by ultrasound, cystoscopy or MRI). As with PAE and PAC, percutaneous ablations are recent innovations requiring validation and comparison with existing techniques.

References:
1. Yu, H., Isaacson, A., & Burke, C. (2016, September). Review of current literature for prostatic artery embolization. Retrieved March 13, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005086/
2. Mitchell M E, Waltman A C, Athanasoulis C A, Kerr W S Jr, Dretler S P. Control of massive prostatic bleeding with angiographic techniques. J Urol. 1976;115(6):692–695.

3. DeMeritt J S, Elmasri F F, Esposito M P, Rosenberg G S. Relief of benign prostatic hyperplasia-related bladder outlet obstruction after transarterial polyvinyl alcohol prostate embolization. J Vasc Interv Radiol. 2000;11(6):767–770

4. de Assis A M, Moreira A M, de Paula Rodrigues V C. et al.Prostatic artery embolization for treatment of benign prostatic hyperplasia in patients with prostates > 90 g: a prospective single-center study. J Vasc Interv Radiol. 2015;26(1):87–93.

5. Yu, Z., Yan, H., Xu, F., Chao, H., Deng, L., Xu, X., . . . Zeng, T. (2020, May 8). Efficacy and side effects of drugs commonly used for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. Retrieved March 13, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225336/

6. Mouli S, Hohlastos E, Salem R. Prostate Artery Embolization. Semin Intervent Radiol. 2019;36(2):142-148. doi:10.1055/s-0039-1688431

7. Maclean D, Maher B, Modi S, et al. Prostate artery embolization: a new, minimally invasive treatment for lower urinary tract symptoms secondary to prostate enlargement. Ther Adv Urol. 2017;9(8):209-216. Published 2017 Jul 10. doi:10.1177/1756287217717889

8. Russo GI, Kurbatov D, Sansalone S, Lepetukhin A, Dubsky S, Sitkin I, Salamone C, Fiorino L, Rozhivanov R, Cimino S, Morgia G. Prostatic Arterial Embolization vs Open Prostatectomy: A 1-Year Matched-pair Analysis of Functional Outcomes and Morbidities. Urology. 2015 Aug;86(2):343-8. doi: 10.1016/j.urology.2015.04.037. Epub 2015 Jul 18. PMID: 26199151.

9. Abt D, Hechelhammer L, Müllhaupt G, Markart S, Güsewell S, Kessler TM, Schmid HP, Engeler DS, Mordasini L. Comparison of prostatic artery embolisation (PAE) versus transurethral resection of the prostate (TURP) for benign prostatic hyperplasia: randomised, open label, non-inferiority trial. BMJ. 2018 Jun 19;361:k2338. doi: 10.1136/bmj.k2338. PMID: 29921613; PMCID: PMC6006990.

10. Zumstein V, Betschart P, Vetterlein MW, Kluth LA, Hechelhammer L, Mordasini L, Engeler DS, Kessler TM, Schmid HP, Abt D. Prostatic Artery Embolization versus Standard Surgical Treatment for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis. Eur Urol Focus. 2019 Nov;5(6):1091-1100. doi: 10.1016/j.euf.2018.09.005. Epub 2018 Oct 3. PMID: 30292422.

11. Stężewska A, Stężewska M, Żabicki B, Salagierski M. The application of prostate artery embolization in the management of intractable prostate bleeding. Cent European J Urol. 2020;73(3):328-335. doi:10.5173/ceju.2020.0149

12. Pisco J, Bilhim T, Costa NV, Ribeiro MP, Fernandes L, Oliveira AG. Safety and Efficacy of Prostatic Artery Chemoembolization for Prostate Cancer-Initial Experience. J Vasc Interv Radiol. 2018 Mar;29(3):298-305. doi: 10.1016/j.jvir.2017.10.013. Epub 2018 Jan 17. PMID: 29352696.

13. Culp SH. Prostatic Artery Chemoembolization-A Viable Management Option for Men Diagnosed with Prostate Cancer? J Vasc Interv Radiol. 2018 Mar;29(3):306. doi: 10.1016/j.jvir.2017.11.006. PMID: 29455873.

14. https://podcasts.apple.com/us/podcast/ep-78-is-radioembolization-future-option-for-prostate/id1448283964?i=1000489017607

Coil Embolization Innovations
September 25, 2021

Author(s):
Rajat Mohanka
NYIT College of Medicine ’24

Harris Liou
Mayo Clinic Alix School of Medicine ’23

Hamad Khalil Hamad
Geisinger Commonwealth School of Medicine ’23

The use of bleeding control procedures goes back throughout history, but the modern era of medicine has ushered in new minimally invasive ways to stop bleeding. Common techniques in World War 2 were vessel ligation or ultimately amputation. Since WW2, there has been an increase in hemorrhaging control technique advancements, especially in emergent and traumatic situations. Embolic agents were created to increase the effectiveness of controlling bleeds without invasive procedures. In the early 1970s, the embolizing vascular injuries from trauma was first described by Rosch and Dotter, with a follow up from Bookstein and Goldstein a year later.

An increasing number of  interventionists are being integrated into emergency procedures to prevent hemorrhaging in a safe and efficient manner, given the high success rate of using embolization techniques. Embolization techniques have expanded quickly from hemorrhage control to treating endovascular disorders such as aneurysms.

One form of embolization is balloon embolization, which was once used in controlling aneurysms (first described in 1974 by Serbinenko). But as years went on, the downside of using balloon embolization was seen as balloons forcing the aneurysm to adapt to the shape of the balloon, which had a high incidence of aneurysm rupture. This changed in 1988, when Hilal first used coils as an embolization technique to treat aneurysms. Coil embolization is a technique of passing metal coils within the vessel of abnormal blood flow. Once detached and inserted in the region, the coil will adapt around the aberrant vessel to occlude blood flow to that vessel. This became a prominent technique used in treating aneurysms due to the reduced pressure on the blood vessel walls relative to the balloons     .

Building on his prior advances, in 1989 Guglielmi first developed a GDC (Guglielmi-detachable coil) embolization system. The embolic material is a soft platinum coil that is passed through the vessel via a catheter or microcatheter. The coil is then positioned (can be readjusted if not in the correct position). Then a current is stimulated which results in the release of the coil into the aneurysm. The first GDC coil was used in a clinical setting around 1990 to treat a carotid artery aneurysm.

The coils used in current coil embolization procedures are made of soft platinum or steel and range in length from 1 to 300 mm and in diameter from 1 to 27 mm.  The coil shapes include straight, helical, tornado, conical, J-shaped, C-shaped, and complex three-dimensional shapes.  The coil can be bare or embedded with fibers, such as nylon, wool, silk, or Dacron to increase coagulation.  Generally, the coil is placed into a catheter and the catheter is inserted into an artery, usually the femoral artery.  The catheter is then advanced to an aneurysm or other affected blood vessel using X-ray guidance.  When the catheter reaches the appropriate area, the coil is released from the catheter into the aneurysm or vessel.  A blood clot will form around the coil, resulting in filling of the aneurysm or total obstruction of the vessel.

This procedure has a growing number of important applications in various fields of medicine.  Transcather arterial embolization is now one of the firstline interventions for massive arterial bleeding from the upper GI, which can be resistant to endoscopic therapy and has a high mortality rate when treated with surgery.  Arresting the bleeding can be achieved either by coiling proximal vessels to the bleed or the preferred method of superselective catheterization where distal vessels immediately supplying the bleed are identified and coiled.  Arterial embolization is considered safe above the ligament of Treitz due to the high collateral supply to the stomach and duodenum.  Transcather arterial embolization is also one of the first line treatments for closing the patent ductus arteriosus, whereby a catheter is used to deliver a Gianturco coil to the aortic side of the ductus arteriosus.  Additionally, the procedure is used to treat intractable severe hematuria due to hemorrhagic cystitis and/or prostate cancer.  The success rate of this operation depends on being able to locate the visceral or prostatic artery responsible for the bleed.  After catheterization of the femoral artery with a 5Fr or 6Fr sheath, selective angiography of the internal iliac arteries is done using a 5Fr Cobra or the Simmons-type 2 catheter.  Based on the angiography findings, a superselective 3Fr coaxial microcatheter is used to deliver platinum microcials to the culprit vessel. In patients receiving hemodialysis via an arteriovenous fistula endovascular coil embolization is used to occlude competing collateral veins, which can lower flow rates and thereby hamper effective hemodialysis. Coil embolization also found high success in treating chylous leaks that occur above the diaphragm.  In this procedure, a microcatheter delivers coils and glue matrix to the chyle leakage site, thereby occluding it.  In patients preparing to undergo liver resection, portal vein embolization is used to redirect blood flow to the future liver remnant, causing it to hypertrophy and improve its functional reserve.  Lastly coil embolization can be used to block or reduce blood flow to tumors, reducing their access to oxygen and nutrients and thereby causing them to regress and/or reducing their growth potential.

Building on its origin as an effective method to stop hemorrhage, coil embolization continues to improve medicine, having significantly expanded its indications and techniques. Small microcatheters and innovative coil designs have allowed practitioners to provide increasingly safe and effective treatment to high-risk patients. Research is active in many facets of coil embolization, as the field demonstrates its potential to add value to and minimize complications in patient care.

Balloon-assisted coiling is an evolving technology that allows for the temporary inflation of a balloon catheter over the neck of an aneurysm during coil placement. Ideal for intracranial aneurysms, this technique increases coil packing density and reduces procedure time. Recent advancements include increased compliance (conformity to the vessel anatomy), higher inflation and deflation speeds, and increased visibility. New products with novel features continue to be developed and evaluated.

A recent innovation similar to balloon-assisted coiling is the use of non-occlusive remodeling nets. Its indications and functionality are similar to those of balloons, but this patent stent-like device allows for continued blood flow through the vessel during coil placement. This significantly reduces the risk of ischemia to downstream tissues, which has been reported as a complication of balloons. Several other stent-like technologies have been introduced and are under further development.

Design and diversity of coils have had a long history of innovation since the conception of coil embolization. Recently, hydrogel (a material that expands in liquid) was applied to platinum coils to increase packing density and occlusion upon placement. Although these coated coils were effective at lowering hemorrhage recurrence, they were limited by stiffness and restricted placement time. Nonetheless, new designs have incorporated softer coils and delayed expansion times to address these issues.

There are other materials which seek to revolutionize embolization techniques beyond the use of coils.  Researchers have developed a bioactive decellularized cardiac extracellular matrix‐based hydrogel to address the shortcomings of coil embolization. Designed to take on a semi-solid state under pressure, the hydrogel can be injected through catheters and instantly solidified upon ejection into the target. The solid gel can then reliably stop blood flow without depending on the patient’s coagulability or causing imaging artifacts. Trials on pigs have demonstrated the material’s ability to induce a fibroinflammatory response at the embolization site, after which it biodegrades. Importantly, it is producible at a lower price than traditional coils and can thus add value to patient care. Representing a recent rise in research on liquid embolic agents, this innovation holds great potential to improve the practice of embolization.

There are also emerging techniques to aid in embolization planning via e simulation with accurate 3D printed vascular models based on patient imaging. For example, interventional radiologists at UCLA recently reported 3D printing a silicone model of a superior cerebellar artery aneurysm, on which they tested different stents before selecting one to assist in the actual coil embolization. Although such simulations are limited in several regards, such as inaccurate replication of vessel elasticity, improvements in 3D printing technology may allow for better interventional planning in the near future.

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