Servier – Phlebolymphology

Paola Ortiz, MD
E.C.S.A Uruguay Vein Center, CoDirector; Hospital Pasteur Vascular
Surgery/Phlebology Department,
Montevideo, Uruguay; Member of the
Hackett Hemwall Patterson Foundation
Board of Directors, Wisconsin, USA;
Member of the Naples Cardiac and
Endovascular Center faculty staff on the
Hands-on courses, Naples, Florida, USA

ABSTRACT

The treatment of chronic venous disease (CVD) has evolved since its inception in 1891, when Trendelenburg introduced the saphenofemoral junction ligation. In 1905, Keller performed the first saphenectomy and, for over a century, arch ligation flush ligation of the junction and saphenectomy have been the methods of treatment. In 1999, the United States Food and Drug Administration approved the treatment of CVD by means of endovenous thermal ablation. These endovenous techniques are currently the preferred choice due to their minimally invasive characteristics, resulting in less pain during and after the procedure, and a faster postsurgical recovery.

Nonthermal nontumescent (NTNT) techniques have arisen in the last 15 years as an even less invasive option for treating CVD, as they do not require the use of thermal energy nor tumescent anesthesia with the benefit of being able to be performed on an outpatient basis. Mechanochemical ablation with ClariVein or Flebogrif catheter is one of the NTNT methods. Endovenous treatments have replaced conventional surgery in the United States and most European countries. In recent years, we have witnessed significant progress in initiatives, knowledge, experience, and availability of technology for treating CVD through endovenous techniques in Latin America. However, there are still several regions in Latin America and around the world where the implementation of these techniques has not yet been fully achieved due to the considerable social and economic variability of the countries. Conventional surgery remains the most prevalent choice in most Latin American countries, accompanied by long waiting lists in many of them. Venous disease has a high prevalence in the population, significantly impacting on the patient’s quality of life and the health system. In many countries, it remains an unresolved health issue.

Thermal ablation techniques, when available, are predominately conducted in hospitals, whereas NTNT techniques are performed in outpatient settings, which may be an advantage in reducing waiting lists for varicose vein surgery. In this paper, we will briefly review the topic and the published literature on NTNT focused on MOCA methods. We will also share experiences and analyze the benefits of NTNT techniques in the Latin American population.

Introduction

Chronic venous disease (CVD), as defined by the Vein Term consensus document, encompasses any morphological and functional abnormalities of the venous system of long duration (especially in the lower extremities), and chronic venous insufficiency (CVI), a term reserved for advanced clinical stages (C3-C6),¹ exhibits a high prevalence and incidence worldwide according to epidemiological studies.^2,3

The international survey program “Vein Consult” (2010)² estimates a prevalence of CVD of clinical stages C0-C6 at 83.6% and a prevalence of C1-C6 at 63.9%. In the DETECT–IVC 2006 study conducted in Spain in 2006, the prevalence of CVD was reported as 67.3%.³ In Latin America, the prevalence of CVD was 68.11%, with 26.6% corresponding to stages C3-C6; the Latin American countries included in that survey were Brazil, Colombia, and Mexico.⁴

At present, insufficiency of the superficial venous system can be treated conservatively by compression and venoactive drugs, as well as by ablative invasive treatment options, including modern open surgery (ultrasound guided) with saphenous vein stripping by invagination and flush ligation of saphenous femoral and popliteal junctions and phlebectomy, and endovenous treatments.^5-7

Endovenous treatments are the recommended first-line treatment for CVD, according to the latest European and American guidelines.

Thermal techniques using radiofrequency ablation (RFA) and endovenous laser ablation (EVLA) were the first ones to receive US Food and Drug Administration (FDA) approval in 1999 and 2002, respectively. They have shown remarkable success in achieving anatomical closure of the great saphenous trunk (GSV) in the long term^8,9 and have been associated with less pain during and after the RFA procedure and a faster postsurgical recovery compared with saphenous vein stripping.^9-11

Nonthermal nontumescent (NTNT) techniques are procedures that do not require the use of tumescent anesthesia nor do they require thermal energy. They include mechanochemical ablation (MOCA), cyanoacrylate closure (CAC), and chemical ablation with ultrasound-guided sclerotherapy (UGFS).

Two devices are available for MOCA: one using liquid sclerosant, polidocanol or tetradecyl sulphate sodium (STS) and a ClariVein catheter (Merit Medical, South Jordan, Utah, USA),¹² and another using sclerosing foam made with polidocanol or STS and a Flebogrif device (Balton, Warsaw, Poland).¹³

For CAC, there are 3 devices on the market: VenaSeal (Medtronic, USA),¹⁴ VariClose (Biolas, Turkey),¹⁵ and VenaBLOCK (INVAMED, Turkey),¹⁶ presenting different polymerization characteristics.

For UGFS, there is physician-compounded foam performed with the Tessari technique¹⁷ and polidocanol endovenous microfoam (PEM).¹⁸

All these endovenous methods and devices are supported by studies demonstrating their effectiveness and feasibility. They have a low incidence of periprocedure pain^9,19,20 and a low risk of neurological adverse effects.²¹

The rate of anatomical closure varies among these techniques. Important key points to achieve a successful closure for a long period of time is the proper selection of the patient—the diameter of the vein to be treated is crucial—and an optimal performance of the technique.

The rate of anatomical closure of CAC is similar to thermal techniques in the medium term.22 The anatomical success of UGFS is better in saphenous trunks under 6 mm of diameter, although these results depend on the strategy and technique applied, which is very variable.²³

MOCA techniques include 2 types of catheters with different mechanisms of action, therefore they should be analyzed separately. Results of MOCA with the ClariVein catheter techniques improve in saphenous trunks under 8 mm of diameter.²⁴ The European Society for Vascular Surgery guidelines recommend thermal ablation (TA) for the treatment of GSV of ≥12 mm in diameter (IIaC).⁶

Endovenous treatments are recommended as the first line approach by both American (American Venous Forum [AVF], American Vein & Lymphatic Society [AVLS], Society for Vascular Surgery [SVS])^5,7 and European (European Society for Vascular Surgery (ESVS) guidelines.⁶ The current recommendation is grade I, level of evidence A (IA) for TA of the GSV, IIaA for CAC, and IIbA for MOCA. For the small saphenous vein (SSV), the recommendation from the European guidelines⁶ is IA for TA, and IIbB for CAC, MOCA, and UGFS (NTNT methods). For the accessory anterior saphenous vein (AASV), the recommendation is IIaC for TA and IIbB for UGFS; there is still no recommendation for the AASV with CAC or MOCA.^5-7

In this paper, we will analyze a review of literature about MOCA. The literature analyzed in this paper derives from searches conducted using PubMed and Cochrane Embase databases, employing the following keywords: “Ablation Techniques” AND “Saphenous Vein” OR “Varicose Veins” OR “Venous Insufficiency” AND “MOCA”. These searches were carried out in 2 periods, one in December 2023, and the other in February 2024. Additionally, we have also analyzed meta-analysis studies arising from another search performed by a scientist specialized in the subject and basic sciences.

We have selected 35 articles that include outcome studies with MOCA, in addition to 4 randomized clinical trials (RCTs) comparing MOCA versus EVLA and 3 RCTs comparing MOCA versus RFA. We have also analyzed meta-analyses, including one comparing all thermal and nonthermal techniques and saphenectomy. We have examined the results from these articles, highlighting the following information.

Outcome studies with MOCA
Great saphenous vein
In relation to the closure of the GSV at 1 year with ClariVein catheter, the results vary according to different studies, but range from 84.5%²⁵ to 92%.²⁶ Additionally, the closure rate for the SSV at 1 year is reported to be 92.6%.²⁷

From the meta-analysis published by Sun et al in 2017,²⁸ 101 studies were identified, 14 of which met the criteria for inclusion, and it was concluded that MOCA with ClariVein catheter proved to be effective in the short term with minimal complications. The analysis also emphasized the need for standardized consensus guidelines and definition of reports in order to facilitate comparison with other techniques.

From the study published by Witte et al in 2017, it was concluded that after a mean of 36 months of follow-up of patients who underwent MOCA with ClariVein catheter for the treatment of GSV insufficiency, the rate of recanalization occurred in 15% of the 102 successfully treated patients. The anatomical success rates were 92%, 90%, and 87% at 1, 2, and 3 years, respectively. This represents the longest follow-up study of patients who underwent MOCA with the ClariVein catheter. This study demonstrates that MOCA with ClariVein catheter is effective in the medium term, but the outcome seems to decline over time.²⁶

From the analysis of an RCT published by Vähäaho et al in 2019²¹ comparing the results of GSV closure obtained with MOCA versus EVLA and RFA (TA), involving 117 patients, the success of closure at 1 year was 100% for TA and 82% for MOCA (P=0.002). The preoperative GSV diameter was associated with the recanalization rate of the proximal GSV in the MOCA group. At 1 year after treatment, disease-specific life quality was similar in the 3 groups. The GSV occlusion rate 1 year after treatment was significantly higher after EVLA and RFA than after MOCA. Quality of life was similar for both groups.²¹ The conclusion of this study was that the failure of closure in the group of NTNT ablations was linked to the diameter of the vein.

From the 2-year results of a multicenter RCT comparing MOCA with ClariVein catheter to RFA in the treatment of primary GSV incompetence (MARADONA study), that included 213 patients, it was concluded that treatment with MOCA with ClariVein catheter resulted in more anatomic failures mostly driven by partial recanalizations, more hyperpigmentation, but less postoperative pain and a faster improvement in venous clinical severity score (VCSS). Both techniques were associated with similar clinical outcomes at 1 and 2 years.²⁹

Results of the RCT study published by Vähäaho et al in 2021,²⁴ involving 117 patients, comparing EVLA and RFA (TA) versus MOCA with ClariVein catheter, show that at 3 years the occlusion rate was significantly lower with MOCA with ClariVein catheter than with either EVLA or RFA (82% vs 100%; P=0.005). Quality of life was similar between the groups. In the MOCA group, GSVs that were larger than 7 mm in diameter preoperatively were more likely to recanalize during the follow-up period. The partial recanalizations of proximal GSV observed at 1 year progressed during the follow-up.²⁴ The authors concluded that MOCA with ClariVein catheter is a feasible treatment option in an outpatient setting, but its technical success rates are inferior compared with endovenous thermal ablation. Its use in large-caliber veins should be considered carefully.²⁴

A meta-analysis and systematic review published in 2022,³⁰ comparing MOCA with the ClariVein device with TA, showed that MOCA is as effective as standard TA within the first postoperative month. However, this approach was associated with less success after 12 months; in most studies, pain was less severe in cases of MOCA. This data suggested that MOCA was safe for varicose veins. However, large-scale and long-term studies are required to define the role of MOCA.

The MOCA technique by Flebogrif shows, according to the published studies, a closure success of up to 93.2% at 1 year. This information comes from a systematic review and meta-analysis of MOCA using the Flebogrif device (Balton, Warsaw, Poland) for varicose veins, recently published by Alozai et al, in 2022.³¹

In this meta-analysis, 5 articles met the criteria for inclusion, reporting 348 procedures in 392 patients. Closure success at 12 months was 93.2% (95% CI, 90.3%-96.1%). This study concluded that MOCA using Flebogrif catheter was a safe and well-tolerated treatment for GSV insufficiency. However, well-designed studies with a higher number in follow-up are required to compare the effectiveness with other modalities, and thus define the definitive role of the Flebogrif device.³¹

Small saphenous vein
For the SSV, the results of treatment with MOCA appear to have similar closure success to that of GSV treatment. According to the retrospective study of 60 patients with SSV incompetence treated with ClariVein in a single center published by Baccellieri et al in 2021, the closure success at 1 year was 92.6%.²⁷ In the prospective cohort study published by Boersma et al in 2013, with 50 patients treated with the ClariVein device, the 1-year follow-up with Echo-Doppler showed an anatomical closure success of 94% (95% CI, 0.87-1).³²

In a comparative retrospective study of treatment of the SSV with MOCA with ClariVein catheter versus saphenopopliteal junction ligation and stripping published by Apruzzi et al in 2022,¹⁹ involving 118 limbs, at 10 months follow-up, the closure success rates were similar (recurrence rates were 7.5% [4/53] for MOCA vs 5.7% [3/52] for the stripping group), but the report of 3.4% of neurological adverse effects in the stripping group was noteworthy. In the MOCA group, there were no neurological adverse effects, less postoperative pain was reported, and the patients returned faster to their usual activities (MOCA 3.5 ± 2.3 days vs open surgical treatment [OS] 14.2 ± 3.8 days, P<0.0001).¹⁹

In the meta-analysis of mechanochemical ablation with Flebogrif, 3 of the 5 studies analyzed reported a closure rate of 90% to 96% at 1 year³¹; Iłźecki et al performed the longest follow-up, with an occlusion rate of 93% after 24 months.³¹

Sclerosant dose in MOCA
From this review of the literature, we have found studies providing important technical and histological information that may help physicians to choose the proper technique and dose of sclerosant for performing MOCA.

A notable study is the double-blind multicenter RCT trial published by Lam et al in 2022³³ with a follow-up period of 6 months, which evaluated the technical outcome (defined as an open part of the treated vein segment of ≤10 cm in length) of MOCA of 375 GSVs treated with ClariVein catheter using polidocanol at different concentrations and different vein diameters. The technical outcome at 6 months was 69.8% in the 2% polidocanol group versus 78.0% in the 3% polidocanol group (P=0.027). A better technical outcome was observed in GSV of ≤5.9 mm compared with GSV of >5.9 mm (84.3% vs 59.5%, respectively P<0.001). In that study, 2 pulmonary embolisms and 2 deep venous thromboses were seen. Superficial venous thrombosis occurred more often in the 3% group (18 vs 8 in the 2% group; P=0.033).³³

The results of this study show better closure success for ClariVein catheter with 3% polidocanol in liquid form compared with ClariVein catheter with 2% polidocanol in liquid form at a 6-month follow-up. However, the difference in quality of life was not significant. Long-term studies are required to investigate whether these results are sustainable over time.³³

Other advantages of MOCA
MOCA of the GSV has the advantage of being an ablation without tumescent anesthesia and without thermal ablation, thus making it a less painful procedure.^27,34,35

In addition, MOCA is associated with a significant improvement in VCSS and in health-related quality of life (HRQOL) measured in several studies.

A retrospective study published by Kim et al in 2019³⁶ was conducted in 66 patients with venous leg ulcer (VLU). Seventy-four percent of patients who underwent MOCA with ClariVein catheter achieved ulcer healing, in comparison with 35% of those treated with EVLA and RFA (TA). The mean time to heal was 4.4 months in the TA group, compared with 2.3 months with MOCA (P=0.01). However, there were notable differences between treatment groups. Patients who received MOCA were significantly older than the TA group (mean 67.9 vs 57.2 years, P=0.0003), and a greater proportion of MOCA patients had multiple vein segments treated (63% vs 16%, P=0.0010). The MOCA group had more treatment of the SSV and perforator veins (P<0.05). The duration of venous ulcers was slightly longer in the MOCA group (mean 11.2 ± 14.4 months vs 9.2 ± 13.9 months in the TA group, P=0.5414). The length of follow-up was longer in the TA group (mean 12.8 months, range 0–46 vs mean 7.9 months, range 0.5–20; P=0.0220). This study concludes that MOCA is an effective and safe technique in the treatment of venous ulcers and appears to provide results comparable to TA. According to this study, young age of patients and the use of MOCA promotes wound healing. MOCA, in this study, was an independent predictor of ulcer healing. However, RCTs are required to further support these findings.³⁶

The feasibility and effectiveness of the MOCA techniques have also been shown in the treatment of venous malformations such as Klippel-Trénaunay syndrome (KTS), as evidenced in the study conducted in Argentina for the treatment of children with KTS, published by Lambert et al in 2021.³⁷

Systematic reviews and meta-analysis comparing thermal vs NTNT techniques
A health-technology assessment of CAC and MOCA was conducted in Ontario, Canada in 2021,³⁸ evaluating effectiveness, safety, and cost-effectiveness among other issues. This systematic review and meta-analysis included 19 primary studies reported in 25 publications comparing either MOCA or CAC, with at least one other invasive treatment for symptomatic varicose veins. No studies compared MOCA with CAC. All RCTs up to 2021, since January 2012, were included.^21,24,29,35 Findings from this meta-analysis included the following: MOCA and CAC were shown to be equally effective in achieving clinical improvement and enhancing the quality of life compared with TA. CAC demonstrated a similar anatomical closure outcome, whereas MOCA exhibited poorer anatomical closure outcomes. Recovery time was slightly reduced with nonthermal endovenous procedures compared with TA. The complication profiles of both nonthermal endovenous procedures were generally minor, though the nature of adverse events differed somewhat from those following EVLA or RFA, as expected. Most adverse effects were mild, transient, and resolved either entirely or to a point of being a minimal interference with people’s lives. However, most studies that reported complication data were not powered to statistically test differences in complications between treatment groups. EVLA was most likely to be the most cost-effective strategy.

In patients with ulcers, MOCA presented a similar anatomical outcome compared with RFA and EVLA. In patients with active ulcers, MOCA showed a higher ulcer healing rate among patients with similar healing time and recurrence.^36,38

In this meta-analysis, the publication of Vähäaho et al in 2019²¹ is highlighted, which describes a significant association between the preoperative diameter of the GSV and the success of closure in the proximal segment of the GSV. The mean diameter of patients who reported recanalization of proximal thigh at 1 year was 8.6 mm, compared with those who did not recanalize, which was 6.5 mm.^21,38

A study published by Shaprynskyi VO et al in 2023³⁹ compared the treatment of CVD with superficial venous insufficiency in 228 patients with C2-C6 stages using EVLA, RFA, MOCA, CAC, and UGFS. EVLA was demonstrated to be the most effective method for treating CVD, providing the best long-term results. The advantage of NTNT techniques was that they do not injure the perivascular tissue or spaces, and there was no need of tumescent anesthesia—this is important in cases of patients allergic to anesthesia. Additionally, after applying cyanoacrylate, no compression stockings were required. Foam sclerotherapy had the advantage of lower cost compared with other methods, and it was used to address postoperative technical failures associated with other methods.³⁹

A meta-analysis comparing MOCA with endothermal ablation that included 4 RCTs comprising 654 patients was recently conducted and published in April 2023.⁴⁰ A lower occlusion rate at 1 year was observed after MOCA than with TA (risk ratio 0.85, 95% CI, 0.78 to 0.91; P=0.001). No significant differences were observed in procedural or postprocedural pain. No significant differences were observed in Aberdeen Varicose Vein Questionnaire score at 1 year (mean difference 0.06, -0.50 to 0.62; P=0.830) or incidence of venous thromboembolism (risk ratio 0.72; 95% CI, 0.14 to 3.61; P=0.690).

Summary of the literature
In summary, whereas most of the studies have involved a low number of patients and are not RCTs, MOCA techniques offer the advantages of being associated with fewer neurological adverse effects, less pain during and after the procedure, faster recovery after the procedure, no need for anesthesia, and that they can be performed on an outpatient basis in clinics. From the analysis of the studies, we can conclude that to obtain good long-term results, patients should be selected based on the diameter of the vein to be treated. The type of sclerosant, along with its concentration, is also crucial. The best outcomes are obtained with veins of 7 to 12 mm, or even smaller diameters, using 3% polidocanol or STS, at least in the proximal segments. The device that uses foam sclerosant has also shown positive results. Better results were observed for patients with ulcers.

It is recommended that randomized control studies, more extensive in terms of sample size and duration of follow up, should be carried out to obtain more conclusive results.

Our experience, progress, and application
of endovenous techniques in Latin America

Latin America exhibits considerable social, political, and economic diversity.⁴¹ In recent years, we have witnessed in Latin America substantial progress as regards the treatment of CVI using endovascular methods.

In many countries, the first option is conventional saphenous stripping surgery in the operating room, and currently, there are long waiting lists to address the venous pathology. The efforts of the medical community and the population, caused in part by globalization, have led to improved accessibility to technical knowledge and devices for treating various pathologies, especially CVI. Nevertheless, there is still a long way to go.

In many areas of Latin America, as well as worldwide, accessibility to invasive treatments is limited and CVD progresses to advanced stages with ulcers and phlebolymphedema, which not only impacts the patient’s quality of life but also has social, economic, and health care system implications for the countries.

The possibility of performing NTNT ablations in authorized clinics enables addressing an unresolved health issue, at least in certain patients, such as those with saphenous veins smaller than 7 mm, as suggested in the literature.

Based on an experience of more than 10 years with NTNT techniques across various centers and academic and humanitarian activities in Latin America, and having performed over 1000 cases of MOCA, we have observed the benefits these techniques may bring to a segment of the Latin American population.

With the support of foundations such as the Hackett Hemwall Patterson Foundation, with headquarters in Wisconsin, the United States of America, and the Naples Cardiac and Endovascular Center foundation, along with other foundations working to provide help, we have observed the benefits of MOCA techniques in these activities and in this population.

From the experience and data records of patients assisted by the foundations, it should be noted that, with the aid of donations, 150 MOCA procedures using the ClariVein catheter have been performed annually from 2015 to 2019. In total, 750 ablations were conducted during that period, and we have observed a low incidence of adverse effects, with no instances of deep venous thrombosis, and we also observed self-limited hyperpigmentation. The success of vein closure treated by MOCA techniques during the activities of these 2 foundations was similar to that reported in the international literature. The technique is performed following the guidelines, resulting in an improved quality of life and faster ulcer healing time (Figure 1).

In relation to our experience in private clinics and public hospitals in Uruguay with MOCA for the treatment of CVI, we present an unpublished work conducted at Centro Venoso E.C.S.A., Uruguay. This work aims at determining the effectiveness and feasibility of the NTNT MOCA technique with the ClariVein device in clinics in Latin America, with a 5-year follow-up.

Figure 1. Ultrasound image of a catheter during mechanochemical ablation.

This study shows that, although the success of saphenous vein closure was 86.4% at 5 years (Figure 2), patients experienced an improvement in their quality of life, as measured bythe CIVIQ 20 scale (ChronIc Venous dIsease quality-of-life Questionnaire). The VCSS improved from an average of 12.3 before treatment to 1.7 at 1 year and 1.6 at 5 years (Figure 2). Recanalization was observed in patients with a body mass index (BMI) greater than 30 and saphenous vein diameter greater than 10 mm. All ulcer patients maintained closed ulcers, despite an axial vein closure success rate of 86.4% at 5 years.

We have attached Figure 3 and Figure 4 with the results of another more recent study involving 57 cases of MOCA with the ClariVein device conducted also at Centro Venoso E.C.S.A., Uruguay. This study was aimed at demonstrating the feasibility of performing these procedures in clinics.

Figure 2. Closure rate at 5 years after treatment with mechanochemical ablation (MOCA) (left panel). Evolution of venous clinical severity score (VCSS) at 1 and 5 years (right panel).

The benefits, similar to those reported in the literature, include its feasibility in clinics, rapid return to work, reduced pain, lower incidence of adverse effects and similar closure success rates in the short-term considering the diameter of the vein to be treated and the BMI.

Figure 3. Venous clinical severity score (VCSS) in the studied population A) before treatment with nonthermal nontumescent ablations (mechanochemical ablations) and B) at 1 year after treatment with nonthermal nontumescent ablations (mechanochemical ablations) at Centro Venoso E.C.S.A. Uruguay.

Figure 4. Rate of great saphenous vein closure at 1 year after treatment with mechanochemical ablations (MOCA) at Centro Venoso E.C.S.A. Uruguay.

Benefit for Latin America

Within the framework of the socioeconomic and health system situation in Latin America described above, NTNT and thermal treatments help to reduce the incidence of CVI and the waiting list for surgery, offering an alternative to conventional surgery and the prevalent conservative option in Latin America.

Based on the analysis of the data reported in the literature and our own experience, MOCA techniques are feasible and effective also in Latin America, especially in insufficient veins considering diameters under or equal to 8 mm.

More long-term multicenter randomized comparative trials with a larger number of patients would be needed to support their benefits.

Given the progress achieved in recent years in Latin America, the application of endovenous techniques is a present and promising future solution to address a health problem that remains unresolved.

Conclusions

Although studies have shown that MOCA techniques have a lower anatomical closure rate for large insufficient venous trunks compared with thermal techniques, they have demonstrated a low incidence of adverse effects, less pain before and after the procedure, a rapid return to work and normal daily activities, the possibility of being performed on an outpatient basis in authorized clinics, and an undeniable improvement in the quality of life with similar effectiveness, especially in patients with veins with diameters less than 8 mm.

Although more randomized trials are needed to assess adverse effects and long-term results, MOCA ablations in well-selected patients are currently highly advantageous, as demonstrated in studies conducted so far and in humanitarian activities.

strong>CORRESPONDING AUTHOR
Paola Ortiz, MD,
Gallinal 1374, Montevideo, Uruguay,
ZC 11400
EMAIL: paolaortizmd@hotmail.com


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