Current Treatment Options in Gastroenterology (2014) 12:183–210 DOI 10.1007/s11938-014-0015-x

Endoscopy (I Waxman, Section Editor)

Interventional Endoscopic Ultrasonography Lorenzo Fuccio, MD1 Fabia Attili, MD2 Giuseppe Vanella, MD2 Alberto Larghi, MD, PhD2*

Address 1 Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy *,2 Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy Email: [email protected]

Published online: 8 March 2014 * Springer Science+Business Media, LLC 2014

Keywords Interventional endoscopic ultrasound I Peri-pancreatic collection I Drainage I Biliary access I Pancreatic access I Pelvic collection I Non-peripancreatic collection I Rendezvous approach I Antegrade approach I Transmural drainage approach I Gallbladder drainage I Anti-tumor treatment I Fine-needle antitumoral agent injection I Gold fiducials placement I Interstitial brachytherapy I External beam radiation treatment I Tumor ablation I Radio-frequency ablation I Pancreatic cyst ablation I Vascular interventions I Variceal bleeding

Opinion statement Endoscopic ultrasound (EUS) is not only a diagnostic tool but also an interventional and therapeutic procedure. Indeed, in addition to tissue acquisition, it can also drain fluid collections adjacent to the gastrointestinal tract, provide access to biliary and pancreatic ducts, biliary, pancreatic, and gallbladder drainage, pancreatic cyst ablation, and, finally, provide anti-tumoral treatments and interventional vascular procedures. Although several improvements have been made in the last decade, the full potential of interventional EUS is yet to be completely explored. Future areas of research are the development of dedicated tools and accessories, the standardization of the interventional procedures, and the widening of the use of EUS, while increasing the expertise worldwide. In addition, more data, based on well-performed, possibly randomized clinical trials, are needed to accurately determine the risks and long-term outcomes of these interventions. We firmly believe that interventional EUS can play a pivotal role in anti-tumor treatments, by the fine-needle injection of anti-tumoral agents, tumor ablation, and assisting radiation treatment with gold fiducial placement and the implantation of intralesional seeds. The goal of the near future will be to offer targeted therapy and monitoring of tumor treatment response in a more biologically driven manner than has been available in the past. Interventional EUS will be an essential part of the multidisciplinary approach to cancer treatment.

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Introduction The possibility of performing real-time endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) has transformed EUS from a pure imaging modality into a more interventional procedure. The precision of EUS in targeting adjacent organs and then thrusting a needle into them has naturally stimulated investigators to consider EUS not only for tissue acquisition, but also for more interventional and therapeutic indications. Current interventional EUS procedures include drainage of collections adjacent

to the gastrointestinal tract, access to biliary and pancreatic ducts and drainage, anti-tumoral treatments, and interventional vascular procedures. Recent increasing interest within the industry with the development of accessories specifically designed for EUS will soon take interventional EUS to the next level, paving the road for new and exciting indications and procedures. This paper reviews the present status and current evidence of interventional therapeutic EUS.

Endoscopic ultrasound (EUS)-guided drainage of collections adjacent to the gastrointestinal tract EUS-guided drainage of peri-pancreatic collections EUS-guided drainage is a well-established treatment modality for peri-pancreatic collections. Based on the revision of the 1992 Atlanta classification of acute pancreatitis [1], we now distinguish four types of peri-pancreatic collections: acute fluid collection, pancreatic pseudocyst, acute necrotic collection, and walled-off pancreatic necrosis (WOPN). Peri-pancreatic collections need to be treated when they cause persistent symptoms and/or in the case of infection. It is always important to consider and exclude a possible neoplastic etiology of the collection, especially in cases where the presentation is unusual, making the diagnosis uncertain. EUS-guided drainage has several advantages in comparison with the other treatment modalities. In particular, in a recently published, randomized, controlled trial for pancreatic pseudocyst treatment, EUS-guided drainage was found to be at least as effective as surgery, with less invasiveness as demonstrated by the shorter hospital stay and better physical and mental health of patients, with an additional advantage of cost saving [2••]. In addition, a recently published meta-analysis has demonstrated a significantly overall higher technical success rate for drainage under EUS guidance than with the conventional, blind, endoscopic transmural drainage (CETD). However, for bulging pseudocysts, short- and long-term treatment success rates and complications were similar [3]. In a recent revision of the experience on more than 2000 patients, mean technical and clinical success rates were 97 % and 90 %, with mean overall complication and recurrence rates of 14 % and 8 % [4••]. Based on all of the above experiences it is possible to conclude that EUS-guided drainage represents the treatment of choice for non-bulging pseudocysts, and should also always be used in cases of coexistent portal hypertension or coagulopathy. In all other cases, the choice between EUS-guided drainage and CETD strongly depends on the endoscopist’s preference and on local expertise. In cases of failure of CETD, the possibility of crossing over to EUS-guided drainage should always be kept in mind because it has usually proved to be successful [5, 6]. Technically, drainage of peri-pancreatic collections has to be per-

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formed using a therapeutic linear echoendoscope with at least a 3.7-mm working channel, which allows the insertion of a 10Fr stent or a metallic stent (Fig. 1). Recently, a forward-viewing echoendoscope with the exit of the working channel at the tip of the instrument has been proposed as an alternative to the conventional linear echoendoscope, to overcome some of the limitations of the use of this instrument, which only permits a tangential approach to the pancreatic fluid collections. However, a multicentrer, randomized, controlled trial comparing the performance of these two echoendoscopes in draining fluid collections has failed to demonstrate any significant difference in technical success, mean procedural time, safety, and efficacy between the two endoscopes [7]. The drainage procedure includes four steps: (i) identification of an appropriate puncture site; (ii) puncture and insertion of a guide wire; (iii) creation of a fistulous tract between the gut lumen and the collection; and (iiii) insertion of the drainage device. In regard to this latter issue, the placement of multiple, small plastic stents (7Fr or 8.5Fr), with or without a naso-cystic drainage [5], is now accepted practice. The multiple stents approach is especially useful for collections with a diameter greater than 10–12 cm and when a solid component is detected. In particular, in the case of large WOPNs for which endoscopic therapy has been shown to be significantly more beneficial than surgical treatment [8], the collection can be better approached by performing multiple transmural accesses. In this technique, called multiple transluminal gateway technique, multiple stents are placed in the caudal part and a naso-cystic drainage in the cranial tract of the necrotic collection [9]. This approach has been reported to lead to a better long-term clinical outcome and represents the only factor significantly associated with treatment success of WOPNs in the multiple logistic regression analysis [10]. In another study, the use of a naso-cystic catheter has been associated with lower stent occlusion rates and better short-term clinical outcome, especially in cases of fluid collections containing abundant, viscous, solid debris [11]. Indeed, the naso-cystic drainage allows constant irrigation of the collection and flushing out of the necrotic debris through the multiple gateways in the stomach/duodenum. The use of self-expandable metallic stents (SEMSs) has been recently tested as a possible alternative to the multiple stents approach, in particular for drainage of WOPN and infected collections (Fig. 2). SEMSs provide a larger diameter than plastic stents and, therefore, can theoretically allow for faster drainage, decreased risk of occlusion, and reduced need for repeated procedures. Available data include only case series and pilot studies and, although a publication bias cannot be excluded, all of these studies showed an increased success rate and a reduced time to resolution of fluid collections [12–15]. However, large prospective studies are needed before any recommendation can be made. Finally, successful EUS-guided drainage of peri-pancreatic collections through an unusual site, in patients with altered anatomy and in children, have been also reported [16–18].

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Figure 1. Endoscopic ultrasound (EUS)-guided drainage of a large pancreatic pseudocyst using multiple plastic stents. A: EUS view of a pancreatic pseudocyst that appears full of fluid. B: EUS view of a 0.035-inch guide wire inside the pseudocyst. C: Fluoroscopic view of an 8.5 Fr cystotome inside the pseudocyst after penetration through the gastric and cystic walls. D: Fluoroscopic view of EUS-guided placement of the first 8.5 F 2-cm-long double-pig-tails plastic stent. E: Fluoroscopic view of EUS-guided placement of the second 8.5 F 2-cm-long double-pig-tails plastic stent. F: Endoscopic view of the proximal falanges of two double-pig-tails plastic stents in the gastric cavity.

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Figure 2. Endoscopic ultrasound (EUS)-guided drainage of walled-off pancreatic necrosis (WOPN) using a 15-mm Axios stent to allow endoscopic necrosectomy. A: EUS view of the peri-pancreatic collection containing abundant solid material consistent with a walled-off pancreatic necrosis. B: EUS view of the distal falange of the 15-mm Axios stent after opening inside the WOPN. C: Fifteen-millimeter balloon dilation of the Axios stent to allow endoscopic necrosectomy. D: Endoscopic view of the entrance in the WOPN through the previously placed 15-mm Axios stent. E: Endoscopic view of removal of necrotic material through the Axios stent. F: Endoscopic view of the cavity with granulation tissue after complete necrosectomy.

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EUS-guided drainage of abdominal non-peripancreatic and pelvic collections EUS-guided drainage has also been demonstrated to represent a valid alternative for the management of abdominal [19] (i.e., subphrenic space, perihepatic, left lobe of the liver, perirectal space) and pelvic collections [20, 21]. The latter may represent a clinical challenge because of their location, usually surrounded by major organs, such as the bladder, prostate, vagina, or uterus. The technique is very close to that previously described for the drainage of peri-pancreatic collections; catheter and plastic stents are usually implemented as drainage devices [20, 21]. Published evidence has shown good results both in terms of technical and clinical successes, with mean rates above 90 % and without any procedurerelated adverse events reported [4••].

Pancreatobiliary access and drainage EUS-guided biliary drainage Endoscopic retrograde cholangiopancreatography (ERCP) is the method of choice used for the treatment of biliary obstruction. Percutaneous and, less frequently, surgical decompression are used after failed ERCP, which can occur in up to 5–10 % of cases because of altered anatomy, periampullary diverticulum, tortuous ducts, impacted stones, or tumor infiltration [22]. EUS-guided biliary drainage represents an attractive, less-invasive alternative after unsuccessful ERCP. In a recent, prospective, controlled trial comparing EUS-guided with percutaneous tranhepatic biliary drainage, 25 patients with unresectable malignant biliary obstruction after a failed ERCP attempt in a tertiary care center were randomly assigned either to EUS-guided or to percutaneous transhepatic biliary drainage [23]. Technical and clinical successes were achieved in all patients, with no difference in the incidence of adverse events between the two approaches. These results indicate that EUS-guided biliary drainage is at least comparable to percutaneous drainage in terms of clinical effectiveness, with the great potential to provide a better quality of life for the patients; a very important factor to consider especially in view of their very short life expectancy [23].

Techniques for EUS-guided biliary drainage As with all the interventional EUS-guided procedures, a therapeutic linear echoendoscope is used to achieve the biliary access within a dilated segment of the biliary tree proximal to the site of obstruction. EUS-guided biliary drainage can be performed with either a transgastric-transhepatic (intrahepatic) or transenteric-transcholedochal (extrahepatic) approach (Fig. 3)] [24]. The intrahepatic approach is performed with the echoendoscope positioned in the cardia or lesser curvature of the stomach to allow visualization of the dilated left intrahepatic biliary system. In the extrahepatic approach, the common bile duct is most frequently visualized from the duodenal bulb, but sometimes for anatomical reasons from the distal antrum only. Puncture of the target duct is typically performed with either a 19- or 22-gauge needle. Once proper positioning in the biliary system is confirmed by bile aspiration and contrast injection, a guide wire

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Figure 3. The three potential endosonography-guided cholangiopancreatography access routes: intrahepatic (1, 2), extrahepatic (3, 4), and pancreatic (5, 6). Reproduction with permission from the authors [24].

(0.035, 0.025, or 0.018 inch, different available diameters are used depending on the needle size) can be then advanced into the targeted bile duct. In cases where the guide wire can be manipulated across the ampulla into the duodenum, the procedure can be completed with either a rendezvous or an antegrade approach. If the rendezvous technique is chosen, the echoendoscope is carefully removed while leaving the guide wire in place. A duodenoscope is then passed to the papilla where a snare or biopsy forceps is used to grasp the wire, withdraw it through the accessory channel, and gain retrograde access to the bile duct to complete the procedure as a standard ERCP. In contrast in the antegrade approach, which is normally used when the duodenum cannot be endoscopically reached, a 6 F or 7 F bougie or a balloon catheter is used to dilate the tract, to allow for the passage of the proper accessory (i.e., a stent or a balloon dilator) to perform a direct antegrade EUS-guided procedure at the level of the papilla. In all the other situations in which a guide wire cannot be passed through the ampulla, a fistula is created to allow for subsequent transmural placement of a plastic or metal stent. Creation of the fistula can be done using a flexible needle-knife or a cystotome, while a dilation catheter or a dilating balloon can be used if further dilation of the tract is needed.

Results Since the first reported cases of EUS-guided biliary drainage, several studies have been published and, up to now, over 1000 patients have been treated with technical and clinical success rates of about 90 %, without significance differences between the transhepatic and extrahepatic routes (Table 1) [4••].

The rendezvous and antegrade approaches The rendezvous technique was first described by Mallery and coworkers in 2004 [25]. Since then, several reports, mostly based on a small number of patients performed in expert centers, have been published

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Table 1. Endoscopic ultrasound-guided biliary drainage. Retrospective and prospective studies that included at least 20 patients Authors/Year/Reference

Design

Cases

Technical Success (%)

Clinical Success (%)

Complications (%)

Maranki et al. 2009 [26] Park do et al. 2011 [111] Shah et al. 2012 [28] Iwashita et al. 2012 [29] Dhir et al. 2012 [32] Vila et al. 2012 [43] Horaguchi et al. 2012 [112] Park do et al. 2013 [113] Dhir et al. 2013 [34] Khashab et al. 2013 [27] Gupta et al. 2014 [31] Dhir et al. 2013 [42] Kawakubo et al. 2013 [114]

Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective

49 57 68 40 58 106 21 45 35 35 240 68 64

84 96 85 73 98 70 100 91 97 94 99 97 95

80 89 85 73 98 70 100 87 97 91 87 97 95

18 47 9 12 3 23 10 11 23 14 35 21 42

showing overall clinical success rates of about 65–100 % and complication rates of 4–12 % [26, 27]. Complications included pneumoperitoneum, bile leakage, mild pancreatitis, and acute cholecystitis [27–31]. The theoretical advantage of the rendezvous approach is the ability to avoid the potential risk of bile leakage related to the fistula formation, an advantage that is lost with the antegrade approach. Otherwise, the rendezvous approach presents several limitations: (i) it can be attempted only in patients with accessible papilla, which may be impossible in patients with gastric outlet obstruction or altered anatomy; (ii) even in experienced hands, the average technical success rates is around 75 % [28], and it is associated with prolonged procedural time and the risk of losing access during the scope exchange; and (iii) the need for retrograde cannulation with the need for manipulation of the papilla increases the risk of acute pancreatitis, with a rate similar to the one reported for ERCP [27–30]. Dhir and co-workers performed a retrospective non-randomized study in a highly selective cohort of patients in whom they compared safety and efficacy of EUS-guided rendezvous bile duct drainage with precut papillotomy after failed ERCP [32]. The rate of technical success was significantly higher in the EUS group than in the precut papillotomy group (98.3 % vs. 90.3 %; p=0.03). The only failure in the EUS group occurred in a patient with a pancreatic head tumor and the inability to pass the wire across the biliary stricture. The high success rate reported in the EUS group might partly be explained by the use of a 260-cm guide wire instead of the commonly used 450-cm guide wire to have better steerability, and by the use of small biopsy forceps to anchor the wire in the stomach during wire exchange to prevent incidental slippage. Incidence of complications was similar in the two groups (6.9 % in the precut group vs. 3.4 % in the EUS group, p=0.27), but the severe complications (i.e., severe pancreatitis and bleeding) only occurred in the

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precut group. However, the level of evidence at present is too low to propose the EUS-guided rendezvous drainage technique as an alternative to the precut technique until prospective, multicenter, randomized comparisons about efficacy, complications, and cost are carried out [33]. The same research group published a retrospective study in which the success and complication rates of the intra- and extra-hepatic routes for the EUS-guided rendezvous procedure were compared in 35 patients with distal bile duct obstruction after failed ERCP [34]. Similar technical success rates were observed independently of the approach used, while patients in whom the intrahepatic route was used presented with a higher incidence of post-procedure pain (44.1 % vs. 5.5 %; p=0.017), bile leak (11.7 % vs. 0 %; p=0.228), air under diaphragm (11.7 % vs. 0 %; p=0.228), and a longer hospital stay (2.5 vs. 0.17 days; p=0.015) [34]. These findings further corroborate previously published data by Iwashita et al. [29] who found a technical success rate of only 44 % for the intrahepatic route, with a 25 % complication rate. Several reasons for the higher incidence of complications seen with the intrahepatic route have been advocated. This route involves puncture into the peritoneal cavity followed by puncture of the liver capsule, which together with the respiratory movements of the left lobe might increase trauma at the puncture site/ tract with a consequential higher risk of bile leak and pain. In addition, there is the potential risk of mediastinitis with the transesophageal approach, the risk of injury to the portal vein, and the need for the use of small-caliber stents with a small-diameter delivery device [35]. Although prospective randomized studies are lacking, it seems therefore reasonable to suggest that when both access routes are technically feasible, the extrahepatic should be preferably employed. EUS-guided antegrade treatments include stenting and balloon dilation for both malignant and benign anastomotic strictures and for the treatment of choledocholithisias in patients with unreachable papilla [36–38]. Only a few case reports and case series have been published up to now. The major concern in performing this type of procedure is the high possibility of bile leak through the fistula that has to be temporarily created to allow for passage of the accessories. Complications including mild pancreatitis, abdominal pain, and hepatic subcapsula hematoma have been reported in 0–30 % of cases [36–39].

Transmural drainage approach Direct EUS-guided biliary drainage can be performed through the gastric or the duodenal wall, resulting in a hepaticogastrostomy or choledochoduodenostomy formation. EUS-guided choledochoduodenostomy was firstly described in 2001 by Giovannini and coworkers [40], while hepaticogastrostomy was first reported 2 years later by Burmester et al. [41]. A recently published, multicenter, retrospective analysis that compared success and complication rates in 68 patients undergoing EUSguided biliary drainage via different methods, showed that the complications were significantly higher for the transhepatic route compared with the transduodenal one (30.5 % vs. 9.3 %, p=0.03), and the logistic

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Endoscopy (I Waxman, Section Editor) regression analysis confirmed that the transhepatic route was the only independent risk factor for complications [42]. The most frequently reported complications were cholangitis, bile leak, pneumoperitoneum, and perforation. In addition, three deaths (4.4 %) were also observed always when the transhepatic route was used (two cases with the rendezvous technique and one case when a hepatogastrostomy was carried out). A large, multicenter, retrospective study involving six referral international centers has been recently published [31]. The authors reported their 10-year experience, during which 240 patients (81 % with a malignant etiology) underwent EUS-guided bile duct drainage. The intrahepatic approach was used in 60 % of the cases; while a metal or a plastic stent were placed in 60 % and in 27 % of the cases, respectively. Successful bile duct drainage was achieved in 87 % cases, without significant difference between the extra- and the intrahepatic approaches (84.3 % vs. 90 %; p=0.15). Of note, the intra-hepatic approach performed significantly better than the extra-hepatic for malignant diseases (94.9 % vs. 83.8 %; p=0.01), while no differences for benign diseases were observed. A higher success rate for malignant indications (90.2 % vs. 77.3 %; p=0.02) was noted, which may reflect the larger dilation of the bile duct when a malignant obstruction occurs, with a consequent fixation of the bile duct to the duodenum or the stomach. Complications occurred in more than 30 % of the cases, without significant differences between the extra- and intra-hepatic approaches (32.6 % vs. 35.6 %; p=0.64). The most frequently reported complications were bleeding (11 %), bile leak/peritonitis (10 %), pneumoperitoneum (5 %), and cholangitis (5 %). No significant difference in complication rates was reported between plastic and metal stents. However, a trend towards a better outcome for metal stents was observed. Plastic stents were associated with a higher incidence of cholangitis (11 % vs. 3 %; p=0.02), while bile leak rates were similar between the two groups (9.3 % vs. 9.2 %; p=0.97). It is possible that the high complication rates reported are because of a learning curve effect, the heterogeneity of the techniques used, and the different level of expertise among centers. Based on all the evidence presented above, EUS-guided biliary drainage appears a fascinating technique, with a satisfactory success rate at least in highly experienced centers. However, the lack of specifically dedicated devices may explain the relatively high complication rates observed, which still limits its wide diffusion [43]. Very recently, at the European Congress of Gastroenterology (UEGW 2013) held in Berlin, a multicenter study investigated in 16 patients with biliary obstruction due to malignancy and failed transpapillary drainage, the efficacy of EUS-guided placement of a dedicated dual-flanged lumenopposing stent (Axios; Xlumena, Inc., Mountain View, CA, USA) (Fig. 4) [44]. More technical details on the stent are reported in the following section. The stent was placed in all cases between the duodenal bulb and the extrahepatic bile duct, following needle puncture and guide wire placement. Two stent sizes were used: 6× 8 mm and 10×10 mm (inside diameter×working length). Technical success rate was 94 % (15/16) and

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Figure 4. Endoscopic ultrasound (EUS)-guided biliary drainage using the forward-viewing EUS scope and the Axios fully covered metal stent in a patient with inaccessible papilla because of a malignant duodenal obstruction. A: EUS view from the duodenal bulb of a dilated common bile duct (CBD: 17 mm). B: Puncture of the dilated CBD using a 19-G needle, which evidences the presence of ascites. C: Contrast injection showing a dilated CBD with a distal stricture. D: Fluoroscopic view of a 0.035 guide wire inside the CBD. E: EUS view of the distal falange of the 6- to 8-mm Axios stent opened inside the dilated CBD. F: Endoscopic view of the proximal falange of the Axios stent placed in the duodenal bulb.

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Endoscopy (I Waxman, Section Editor) in all cases the biliary drainage was achieved at the first attempt. Drainage was effective on follow-up in 93 % of patients (14/15) after a mean of 48 days (range: 4–101 days). Two stent-related complications were reported: one duodenal perforation because of stent maldeployment that required stent removal and the defect was closed with clips placement and one case of cholangitis because of sump syndrome (resolved with duct sweep through the Axios). One patient had intraductal bleeding from tumor infiltration and was treated by coil embolization prior to endoscopic intervention, but later died of sepsis owing to bile duct obstruction from blood clots. The majority of patients reported an improvement in their general condition. This initial experience with a dedicated device for EUS-guided drainage showed that it is effective for the treatment of malignant obstructive jaundice in patients in whom transpapillary drainage has failed. Further larger studies are awaited to establish safety and long-term patency.

EUS-guided pancreatic duct drainage EUS-guided pancreatic duct drainage has been suggested after failed or unfeasible ERCP as an alternative to surgery in patients with untreatable abdominal pain due to ductal stones, strictures, or post-surgical stenosis. The procedural steps are very similar to those of biliary drainage. However, EUSguided pancreatic duct drainage is definitively more demanding and challenging than EUS-guided biliary drainage. Technically, EUS-guided drainage of the main pancreatic duct can be achieved by placement of a transmural stent through the stomach or the duodenal bulb, or by doing a rendezvous procedure. The duct is punctured by using a 19- or 22-gauge FNA needle and a pancreatogram obtained thereafter. A 0.035- or 0.020-inch guide wire is passed into the duct, preferably in an antegrade direction into the duodenum or is advanced retrograde to the pancreatic tail. The fistula tract is then enlarged by using sequentially small bougies or a 4.5 F ERCP cannula, followed by balloon dilation with a 4- or 6-mm balloon dilator. Finally, the procedure is terminated by placement of a small-caliber plastic stent via the stomach or the duodenum into the duct. Covered and uncovered metal stents cannot, in fact, be used because they would block side branches leading to obstructive pancreatitis and pancreatic juice leakage, respectively. A rendezvous approach is feasible only if a duodenoscope or a colonoscope can reach the papillary orifice or the site of surgical anastomosis to retrieve the guide wire. Afterwards, the procedure is exactly the same as the one described for the EUSguided biliary rendezvous procedure. Most of the published evidence is case reports and small case series (Table 2). The overall success rate of less than 80 % confirms that this procedure is very difficult and more demanding than EUS-guided biliary drainage [25, 45–51]. Technical failures are mainly because of difficult orientation of the echoendoscope along the axis of the pancreatic duct; inability to dilate the transmural tract because of dense fibrosis caused by the chronic inflammation; and impossibility of stent placement as a consequence of the acute angle of access to the main pancreatic duct. Rate and severity of complications are not negligible, in the range of 3–43 % [47, 50], and include

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Table 2. Results of the studies that retrospectively investigated endoscopic ultrasound-guided pancreatic duct drainage with direct transmural stent placement Authors/year/reference

Cases

Pancreatic duct drainage (%)

Complications (%)

Will et al. 2007 [47] Tessier et al. 2007 [45] Kahaleh et al. 2007 [46] Barkay et al. 2010 [48] Ergun et al. 2011 [49] Shah et al. 2012 [28] Vila et al. 2012 [43] Kurihara et al. 2013 [50] Fujii et al. 2013 [51] Total

12 36 13 21 20 25 19 14 45 205

67 92 77 48 90 86 58 93 73 76

43 55 15 10 20 16 26 7 24 24

serious adverse events such as pancreatitis, pancreatic juice leakage, bleeding, and perforation. Thus, EUS-guided pancreatic duct drainage should be considered only in highly selected cases, with the procedure performed in tertiary-care centers by very experienced echoendoscopists, after adequately informing the patients about the risks, especially when the transparietal stent placement is planned.

EUS-guided gallbladder drainage EUS-guided gallbladder drainage may represent an alternative to percutaneous transhepatic drainage. Ideal candidates are patients with acute cholecystitis unfit for surgery and unresponsive to medical therapy that require decompression of the gallbladder. The gallbladder is punctured from the distal antrum (cholecysto-gastrostomy) or from the duodenal bulb (cholecysto-duodenostomy) using a 19-gauge needle that allows passage of a 0.035-inch guide wire that is coiled in the gallbladder. After dilation of the fistolous tract with a 6 F or 7 F bougie, or with a cystotome, the procedure is finished by placement of a 5 F naso-gallbladder drainage tube or a transparietal fully covered metal stent (Fig. 5). A Korean, randomized, controlled trial has recently evaluated the technical feasibility, safety, and efficacy of EUS-guided versus percutaneous drainage in patients with acute cholecystitis [52••]. Fifty-nine patients with acute cholecystitis refractory to medical treatment and unsuitable for emergent cholecystectomy were randomized to EUS-guided gallbladder drainage by placement of a 5 F naso-gallbladder drainage tube or to percutaneous drainage with an 8.5 F pigtail drainage catheter. Technical (97 % vs. 97 %), clinical (100 % vs. 96 %), and complication (7 % vs. 3 %) rates in the two treatment arms were similar. In addition, in both groups, median duration from drainage to cholecystectomy (5–6 days) and conversion rate (around 10 %) to open cholecystectomy at subsequent laparoscopic cholecystectomy were also similar. Importantly, patients undergoing drainage by EUS had a significantly lower median post-procedure pain score (1 vs. 5; pG0.001). This study has clearly demonstrated that EUS-guided drainage of the gallbladder may represent a good and safe alternative to the percutaneous ap-

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Figure 5. Endoscopic ultrasound (EUS)-guided gallbladder drainage using a fully covered metal stent in a patient with acute cholecystitis with high surgical risk. A: EUS view of the gallbladder with wall thickening and the presence of a big stone. B: EUS view of the distal falange of the 15-mm Axios stent after opening inside the gallbladder. C: Endoscopic view of the proximal falange of the stent in the duodenum with pus coming out. D: Endoscopic view of the gallbladder through the previously positioned stent 2 days after placement. E: Endoscopic view of big stones inside the gallbladder.

proach, at least as a bridge to surgery. Conversely, in high-surgical-risk patients who should avoid undergoing cholecystectomy, a better treatment option could be the EUS-guided placement of a temporary transmural stent that would avoid the placement of a percutaneous drainage with clear ad-

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vantages in terms of quality of life for patients. Recently, a novel lumenapposing metal stent, called Axios (XLumena, Inc.,) has been become available and tested for gallbladder drainage [53, 54]. The stent is a fully covered, nitinol-braided stent with bilateral anchor flanges, available with different diameters (6–15 mm). The silicone covering prevents potential bile leakage and tissue ingrowth, ensuring subsequent removability. The anchors maintain a strong attachment to gastric/duodenal and gallbladder walls, allowing fistula formation, and creation of a stable anastomosis. More recently, a version in which the stent is mounted on a device with a cystotome on the tip is also available (Hot-Axios), rendering the procedure very fast, and safer because rapid deployment of the stent decreases the risk of leakage. Moreover, as pointed out in the biliary paragraph, this stent represents the first stent specifically designed to be placed under complete EUS guidance, with fluoroscopy only used as a back-up. At the present time, 18 patients with acute cholecystitis have been treated with this type of stent [53, 54], with an overall technical success of about 90 % and clinical success achieved in all patients without recurrences during follow-up. Notably, no complications were reported in any case. EUS-guided gallbladder drainage is still a procedure not widely diffused and only performed in highly experienced centers. Therefore, although encouraging results have been reported, more large prospective, multicenter studies are needed before it can substitute percutaneous drainage for definitive treatment of patients with acute cholecystectomy and high surgical risk.

EUS-guided oncologic procedures Interventional EUS as a therapeutic modality directed towards various cancers involves a variety of new and expanding EUS-guided procedures, most of which at present are still experimental. These procedures include EUS-guided fine-needle injection (EUS-FNI), which is an attractive minimally invasive delivery system with potential applications in local (intratumoral) and combination therapy for esophageal and pancreatic cancers; EUS-guided tumor ablation with various techniques such as radiofrequency ablation, photodynamic therapy, laser ablation, and ethanol injection; and EUSguided intratumoral implantation of fiducial markers and seeds to perform image-guided radiation therapy and brachytherapy.

EUS-guided fine-needle injection of anti-tumoural treatments The rationale to perform intratumoral EUS-FNI is the possibility of administering a very high concentration of the target drug directly into the tumor, thus, theoretically increasing the local response and decreasing the concentration of the drug needed to be given systemically or delivering agents with direct cytotoxic activity that are able to promote the immune response against tumor cells. One of the first agents tested is the TNFerade Biologic, which is a replication-deficient adenoviral vector that expresses tumor necrosis factor-α (TNFα), under the control of the Egr-1 promoter, that is inducible by chemoradiation therapy. TNF-α is a potent inflammatory cytokine with potent anti-

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Endoscopy (I Waxman, Section Editor) cancer activity through its effect on tumor vasculature and a direct cytotoxic effect; its clinical use has been limited by its severe systemic toxicity. A multicenter, nonrandomized, phase I/II study investigated the preliminary activity and safety of the combination of TNFerade Biologic with standard chemoradiotherapy in the treatment of patients with locally advanced pancreatic cancer [55]. TNFerade Biologic was injected into pancreatic adenocarcinomas by using EUS or percutaneous guidance. Fifty patients were enrolled and one patient had a complete response, three patients had partial responses, and 12 patients had stable disease. Moreover, seven patients underwent surgery of whom six had a R0 resection, and three survived longer than 24 months. The combination of chemoradiation therapy and TNFerade Biologic was relatively well tolerated. Unfortunately, very recently, the final results of the largest, randomized, phase III trial performed among patients with locally advanced pancreatic cancer comparing standard of care plus TNFerade with standard of care alone, demonstrated that the adjunct of intratumoral injection of TNFerade did not prolong survival at all [56]. Furthermore, the multivariate analysis showed that TNFerade injection by a EUS-guided approach rather than a percutaneous transabdominal approach was a risk factor for inferior progression-free survival. Difficult penetration of a tumor capsule has been suggested as a possible explanation of the dismal results achieved when the EUS route was used. Thus, the variability existing in EUS operator skill across the different participating centers could have substantially influenced the achievement of a homogeneous dispersion of TNFerade throughout large, fibrotic, pancreatic tumors. Conversely, initial evidence on the efficacy of the intratumoral injection of TNFerade with chemotherapy in the treatment of locally advanced esophageal cancer showed encouraging results. A multicenter, phase I, dose-escalating trial was performed in 21 patients; six of them (29 %) had a pathologic complete response and the median overall survival was 47.8 months and the 3- and 5year overall survival and disease-free survival rates were 54 % and 41 %, and 38 % and 38 %, respectively [57]. These promising results need to be confirmed in prospective, randomized, controlled trials. Immunotherapy is a novel approach for pancreatic cancer. Dendritic cells are potent antigen-presenting cells for the induction of primary T-cell-dependent immune responses. It has been speculated that the EUS-guided injection of unloaded dendritic cells into pancreatic cancer cells might induce the acquisition and procession of tumor antigens in situ by the dendritic cells, which can than migrate to regional lymphoid organs and initiate a strong tumor-specific immune response. Up to now, only pilot studies with small sample sizes have been conducted showing promising results [58, 59], especially when a combination strategy (immunotherapy plus systemic conventional treatment) was adopted. EUS can also be used to directly inject systemic chemotherapeutic agents inside the tumor, to enhance the direct drug-specific action and increase the effect of radiotherapy. In 2011, Levy and co-workers presented at the Digestive Disease Week their initial experience on EUS-FNI of gemcitabine in 36 patients with locally advanced or metastatic pancreatic cancer [60]. Gemcitabine, at a dose of 90 mg (range 28–280 mg) was administered as a one-time induction therapy given prior to conventional multimodality therapy. There were no EUS-FNI procedure-related complications or adverse

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events associated with intratumoral therapy. Twenty patients were alive at a mean of about 12 months following treatment initiation and three patients initially deemed unresectable were downstaged and underwent R0 resection. These promising data should be confirmed by controlled, larger studies with longer follow-up, designed to ascertain the impact of EUS-FNI in conjunction with a multimodality strategy on patient survival. EUS-FNI has also been used to deliver a combination of chemotherapeutic agents and a controlled-release delivery system inside the tumor, to increase the drug concentration inside the cancer while reducing the systemic toxicity. OncoGel represents an example; it is an injectable formulation of paclitaxel in a biocompatible biodegradable gel (ReGel) that provides controlled release of the compound at the site of injection. Up to now, there are only few, uncontrolled, available experiences based on small populations that have showed that EUS-guided OncoGel injection is safe and feasible. Indeed, a phase II, dose-escalation study evaluated the toxicity, pharmacokinetics, and preliminary antitumor activity of OncoGel given as an adjunct to radiation therapy in 11 patients with inoperable esophageal cancer [61]. OncoGel provided prolonged paclitaxel release with minimal systemic exposure and seemed to reduce tumor burden as evidenced by dysphagia improvement, tumor size reduction, and negative esophageal biopsies. Although large, controlled, randomized controlled trials are warranted, this initial experience clearly shows that EUS-guided injection of a controlledrelease delivery system in combination with chemotherapeutic agents is an interesting area of future research. Finally, case reports of EUS-guided ethanol injection for the ablation of functional neuroendocrine tumors, hepatocellular carcinomas difficult to treat percutaneously, and left adrenal metastasis from non-small-cell lung carcinoma have been published [62–66]. The available evidence, so far, of EUS-FNI is still weak and this approach remains experimental with a long way to go before it can be translated into clinical practice [65]. However, several trials are on-going (clinicaltrials.gov), thus confirming the strong rationale of this method and the high interest of both researchers and pharmaceutical companies for this very exciting field of research that will also require the development of specifically designed accessories to perform injections in tumors with different characteristics.

EUS-guided gold fiducial placement Radiotherapy is an established treatment modality for patients with several types of cancer (i.e., pancreas) because the combination with chemotherapy provides an improvement in survival. Several target organs are made of soft tissue not visualized on radiographic imaging during radiotherapy treatment planning; therefore bony landmarks are usually used as surrogate markers to localize the organ. However, organs move relative to the bony landmarks, therefore static reference points within the target volume would be helpful. Fiducials are inert radiographic markers, made of gold, that are implanted into the target lesion for both localization and tracking and can serve as a landmark for the delivery of radiation therapy. When available, fiducial placement should be strongly considered, because they improve image guidance for the delivery of radiotherapy to patients with cancer.

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Endoscopy (I Waxman, Section Editor) Several retrospective and prospective case series have demonstrated the feasibility of EUS-guided fiducial placing with reported technical success rates of 88–100 % [67–69, 70•, 71, 72]. The technique of FNI of fiducials is similar to that for FNA. Fiducial seeds may be deployed by 19- or 22-gauge FNA needles [69, 70•, 73]. To preload the needle with the gold fiducials, the stylet is removed from the needle and one or two fiducials are manually back loaded into the tip of the needle; sterile lubrificating jelly or, possibly, bone wax may be used to separate and maintain the fiducial positions within the needle [69]. The optimal number of fiducial seeds that should be inserted into the tumor for adequate Image-Guided Radiation Treatment (IGRT) is still unclear. Generally speaking, a minimum of two fiducial seeds is needed to be distinctly visualized along two orthogonal kilo-voltage viewing planes (i.e., antero-posterior and lateral) and ensure three-dimensional positioning. Once the mass or resection margin has been identified and punctured by the pre-loaded FNA needle, the fiducial seeds are pushed into the tumor by the inner stylet or, alternatively, by a sterile water injection [67, 69]. Complications are not common. The main drawback of EUS-guided fiducial placement is the lack of dedicated accessories; indeed, FNA needles able to carry multiple fiducials, stacked to each other and separated by spacers that can be delivered in one pass are needed; as well as fiducials in different shapes, clearly distinguishable from operative staples.

EUS-guided interstitial brachytherapy The possibility to implant 125I seeds under EUS guidance has recently raised new interest and enthusiasm in the field of interstitial brachytherapy for pancreatic cancer, which was previously almost abandoned because of the dismal results [74]. Studies in both animals and humans have shown EUS-guided interstitial brachytherapy to be feasible and almost safe [75–78]. The procedure is performed using a 19-gauge needle that is placed into the target lesion under EUS guidance. The stylet is then removed, a radioactive seed is inserted inside the needle and then pushed forward and implanted into the tissue by reinserting the stylet. This sequence is then repeated until all seeds are implanted into the target site according to the treatment plan. Placement of the radioactive seeds in the proper position can be complex and requires a high degree of expertise, because positioning them permanently into the wrong tissue may be highly dangerous and prone to fatal complications. Major complications have been unfrequently reported and included cases of hematologic toxicity (grade III neutropenia, thrombocytopenia, anemia) and pancreatitis complicated by pseudocyst formation in two patients [77, 78]. Additionally, cases of seed migration have been observed to the liver, but without serious complications [78]. EUS-guided brachytherapy for unresectable pancreatic tumors alone or in combination with gemcitabine and 5-fluorouracil chemotherapy was associated with 40–50 % of partial or minor responses, with 30 % of the patients experiencing a partial but transitory significant relief of pain [77, 78]. No survival benefit has ever been described. The same Chinese group in a larger patient population subsequently confirmed the effectiveness of EUS-guided brachytherapy on pain control, with a longer follow-up period [79]. Moreover, they also showed the safety and efficacy of direct celiac ganglion irradiation after EUSguided placement of seeds around the ganglia [80]. Of interest, one case of

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complete local remission achieved by a combination strategy of EUS-guided interstitial brachytherapy and chemotherapy of an inoperable retroperitoneal metastatic adenocarcinoma has been described [81]. At present, based on the current limited available data, interstitial brachytherapy should be only considered in conjunction with systemic chemotherapy, specifically as a possible palliative option to relief pain when other strategies have failed.

EUS-guided tumor ablation Radio-frequency ablation Radiofrequency catheter ablation (RFA) is a well-established technique to ablate neoplastic tissue via local thermal-induced coagulative necrosis of the cancer. RFA has been used during laparotomy and by transabdominal ultrasound, but the safety profile and the debatable benefits have strongly limited its diffusion for the treatment of pancreatic cancer. Recent data from the surgical literature, however, have reported that intraoperative RFA performed as a second treatment modality in a multiple adjuvant approach has survival advantages in patients with locally advanced pancreatic carcinoma [82]. This has clearly stimulated the search for a less invasive approach to administered RFA, making EUS the most attractive one. Most of the published evidences on EUS-guided RFA are based on animal studies [83, 84], but results are still limited for human clinical studies. An Italian group has reported its experience with a newly developed, flexible ablation probe combining bipolar RFA and cryotechnology in animals [85, 86] and, more recently, in humans [87••]. This combined technology has been developed with the aim of minimizing the risk of unintended thermal injury in an attempt to overcome the hazard of using RFA in the pancreas without additional cooling of adjacent tissues [88]. The cryotherm probe is an internal carbon-dioxidecooled bipolar RFA probe, covered by a protection tube that can be safely passed through the working channel of a therapeutic echoendoscope. In the only prospective, feasibility, human study currently published, 22 patients with unresectable stage III pancreatic adenocarcinoma were treated [87••]. Cryothermal radiofrequency ablation was feasible in 73 % of the enrolled cases. Failure cases were because of the impossibility of placing the probe inside the tumor owing to stiffness of the gastrointestinal wall or of the tumor itself secondary to the desmoplastic reaction, tumor infiltration, and scar and fibrosis in patients who had already undergone radiotherapy. No deaths or severe complications were reported. One main limitation observed was the impracticality to satisfactorily measure the size of the ablated zone by computed tomography imaging even 4 weeks after treatment, because of the impossibility of distinguishing the intense inflammatory response of the tumor from tumor growth or necrosis. These preliminary data are encouraging, although improvements in the probe and randomized controlled trials are needed. In the future, this technique could represent an additional strategy, together with the standard available treatments for patients who are not surgical candidates.

Nd:YAG laser, high-intensity focused ultrasound, and photodynamic therapy Animal studies on the feasibility of EUS-guided therapies using the neodymium-doped yttrium aluminum garnet (Nd:YAG) laser [89, 90], high-in-

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Endoscopy (I Waxman, Section Editor) tensity focused ultrasound [91], and photodynamic therapy [92, 93] are now available. Di Matteo et al. also experimented with the use of EUS-guided Nd:YAG laser to successfully ablate a hepatocellular carcinoma located in the caudate lobe [94], a location difficult to reach without EUS assistance. Further studies to determine safety and technical feasibility of these techniques in humans are required.

EUS-guided pancreatic cyst ablation Pancreatic cyst ablation with the EUS-guided injection of ethanol, possibly followed by a second ablative agent, paclitaxel, is considered a promising technique for the treatment of premalignant diseases, i.e., mucinous cysts and branch-duct Intraductal Papillary Mucinous Neoplasm (IPMNs), or benign condition, such as serous cystoadenoma, to avoid lifelong monitoring. The cyst is punctured using usually a 22-gauge needle. When possible, the fluid is aspirated up to nearly complete evacuation. Then, ethanol injection is performed with a volume of fluid equal to that initially aspirated, and the cyst is lavaged for 3–5 min, alternately filling and emptying the cavity. At the end of lavage, the injected ethanol is evacuated and a second ablative agent, i.e., paclitaxel, can be injected and left in the cavity. To avoid parenchymal injury or the development of a leak from the cyst wall, it is important to maintain the needle tip within the cyst and the total injection volume should not exceed the volume of the aspirated fluid. The patient’s selection is important to guarantee the highest chance of successful ablation [95]. Only a cyst with a clear benign morphology should be treated. Furthermore, unilocular or oligolocular cysts with fewer than two to three locules represent the best candidates, because in the case of three or more locules, a single needle pass may not provide a sufficient drug delivery to all sites. The diameter should not exceed 4 cm and a minimum diameter of 2 cm may increase the safety profile and the treatment feasibility. Finally, cyst ablation should be avoided when a communication with the main pancreatic duct exists, because the outflow of the injected ablative agent may increase the risk of pancreatitis while reducing the ablative effect. At present, results of clinical trials have been almost disappointing (Table 3), with complete resolution rates of around 30 % [96] with ethanol lavage, rising to 60 % when paclitaxel is added to the procedure [97]. Furthermore, based on the surgical resection specimens, imaging-based resolution may not correlate with histologic ablation and it should be pointed out that long-term follow-up data are still missing; therefore close monitoring is strongly advised even after complete resolution [97]. Although most adverse events are mild and self-limited (i.e., abdominal pain) and the risk of post-procedural pancreatitis is low (2 %), several concerns on the safety profile of the technique still remain. Indeed, cases of venous thrombosis have been reported [98] and the overall amount of patients treated with this procedure (about 150) is still too low to draw any conclusion. Most importantly, there are some concerns about ablation of benign cysts, such as serous cystoadenoma, that can be easily monitored with imaging techniques. Although EUS-guided pancreatic cyst ablation is a promising procedure that may become an alternative to surgical resection, several technical improvements are still needed as well as further well-designed, large

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Table 3. Complete resolution rates after endoscopic ultrasound-guided pancreatic cyst ablation: results of clinical trials Author/Year/Reference

Cases

Ablative Agent

Follow-up Period (months)

Complete Resolution (%)

Gan et al. 2005 [115] Oh et al. 2008 [116]

25 14

6–12 6–23

35 79

Oh et al. 2009 [117]

10

6–18

60

DeWitt et al. 2009 [96] Oh et al. 2011 [97]

42 47

3–4 after second lavage 12–44

33 62

DiMaio et al. 2011 [118]

13

5–80 % ethanol 80 %/99 % ethanol with paclitaxel 99 % ethanol with paclitaxel 80 % ethanol 99 % ethanol with paclitaxel 80 % ethanol

13 after first lavage

38

clinical trials. This treatment should be first directed to a selected patient population in whom the chance of incomplete cyst ablation should outweigh the risks of pancreatic surgery.

EUS-guided vascular interventions EUS-guided vascular interventions have been recently proposed as additional and sometimes alternative procedures for the management of both variceal and non-variceal bleeding of the gastrointestinal tract [99, 100••]. EUS with color Doppler allows the precise identification of vascular anatomy, enables real-time confirmation of delivery of haemostatic substances into the vascular lumen, and allows the monitoring of the injection until obliteration, thus potentially reducing the risk of re-bleeding. Vessel obliteration can be confirmed by the absence of blood flow on color Doppler. One of the main advantages of EUS-guided intervention is the lack of dependency on direct vessel visualization. Even in the presence of blood or retained food that may obstruct the endoscopic view, the vessels can be visualized and targeted for haemostatic agent injection. In addition, it can allow the identification and treatment of occult sources of bleeding such as Dieulafoy lesions and pseudoaneurysms. Most of the published evidence is focused on the treatment of gastric variceal bleeding, which represents the most potential area of interest for EUSguided vascular intervention. The implementation of EUS not only increases the detection of fundal varices up to 6-fold [101], but can also potentially reduce the re-bleeding rate and possibly the mortality. In a retrospective study, Lee and co-workers reported that EUS-assisted cyanoacrylate injection until obliteration of all gastric varices collaterals performed starting 1 week after control of the acute bleeding significantly reduced late recurrent bleeding rate, with a trend toward improved survival [102]. Because of several potentially life-threatening risks of glue embolization following injection of gastric varices [103–105], intravariceal deployment of a stainless steel coil before glue injection has been proposed to reduce these risks [106]. The coil

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Endoscopy (I Waxman, Section Editor) can act as a scaffold to trap the glue within the varix and contribute itself to obliteration and hemostasis, thus decreasing the overall amount of glue needed. This hypothesis has been tested in a multicenter retrospective study in which feasibility, safety, and applicability of EUS-guided coil embolization vs. EUS-guided cyanoacrylate injection were compared [106]. Thirty patients (11 in the coil group vs. 19 in the cyanoacrylate group) underwent EUS-guided treatment for gastric varices. The rate of variceal obliteration was similar and above 90 % in both groups without differences in the number of EUS sessions. However, a significantly higher incidence of complications occurred in the glue group as compared with the coil group (58 % vs. 9 %, pG0.01). In particular, nine patients had asymptomatic pulmonary glue embolism and two patients experienced fever and chest pain, while only one patient treated with coil embolization experienced esophageal variceal bleeding The EUS-guided treatment of gastric fundal varices can also be performed by transesophageal access, with several advantages: the injection can be performed in a straight position, avoiding any potential obstruction from gastric lumen content; the “back-bleeding” effect observed once the needle is removed from the varix can be prevented, and, finally, a more direct access to the feeder vein can be achieved. The access to the gastric fundal varices is through the transcrural route. Binmoeller and co-workers reported their experience in 30 patients who underwent EUS-guided transesophageal treatment of bleeding gastric fundal varices with combined coiling and cyanoacrylate glue injection [107]. EUS-guided transesophageal treatment was successful in all patients. Among 24 patients with a mean follow-up of 193 days, gastric fundal varices were obliterated after a single treatment session in 23 (96 %). Re-bleeding attributed to gastric fundal varices was not observed and, most importantly, there were no procedure-related complications and no symptoms or signs of glue embolization. Taken together, these findings clearly show that EUS-guided coil embolization and glue injection are both effective for gastric varices treatment in patients with cirrhosis and portal hypertension, and the combination of coil embolization and glue injection seems to be safer and more effective than monotherapy. Conversely, EUS-guided sclerotherapy of esophageal collateral veins has shown less impressive results. de Paulo et al. performed a randomized controlled trial comparing the safety and efficacy of EUS-guided procedure with endoscopic sclerotherapy in 50 patients affected by liver cirrhosis and esophageal varices [108]. The authors did not observe any significant difference in variceal eradication, number of sessions needed to achieve the eradication, variceal recurrence, and adverse event rates. Therefore, EUS-guided procedures for the management of esophageal varices should be considered only in refractory cases when conventional treatments have failed. Finally, a few case reports and series have investigated the feasibility and efficacy of glue injection under EUS guidance for the management of nonvariceal bleeding. Levy et al. reported treatment success after EUS-guided embolization of feeding artery of bleeding duodenal artery refractory to other treatment modalities and the successful management of two cases of bleeding from gastrointestinal stromal cell tumors by direct injection of 3–5 mL of glue into the lesion [109]. Fockens and coworkers reported the usefulness of EUS in the diagnosis of small abnormal vessels in eight patients with

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Dieulafoy lesions. In 50 % of cases, it was also possible to perform EUSguided injection of a sclerosing agent into the aberrant vessels [110]. EUSguided treatment for non-variceal bleeding should therefore be considered when other conventional treatment modalities have failed.

Conclusions The possibility of EUS to reach sites difficult to reach otherwise (i.e., mediastinum, retroperitoneum, pelvis) and to thrust a needle or another device into them in a minimally invasive way has naturally allowed EUS to evolve into a more interventional and therapeutic procedure that can be offered as an alternative to other interventional and radiologic procedures. The high technical demands and complexity of EUS-guided interventions will necessitate adequate training and the development of new techniques and specifically designed accessories to facilitate the procedures and decrease the chance of complications. In addition, more data are needed to accurately determine the risks and long-term outcomes of these interventions before clarifying their role. Until then, EUS-guided interventions must be carefully considered and performed by appropriately experienced endoscopists, in tertiary care centers, with the availability of an expert multi-disciplinary team able to take care of possible complications.

Compliance with Ethics Guidelines Conflict of Interest Lorenzo Fuccio, Fabia Attili, Giuseppe Vanella, and Alberto Larghi declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recenlt, have been highlighted as: • Of importance •• Of major importance 1.

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Interventional endoscopic ultrasonography.

Endoscopic ultrasound (EUS) is not only a diagnostic tool but also an interventional and therapeutic procedure. Indeed, in addition to tissue acquisit...
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