ADVANCES IN DIAGNOSTIC AND THERAPEUTIC ENDOSCOPY

ADVANCES IN GASTROENTEROLOGY

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ADVANCES IN DIAGNOSTIC AND THERAPEUTIC ENDOSCOPY Shawn Mallery, MD, and Jacques Van Dam, MD, PhD

Endoscopy has changed the practice of gastroenterology radically. Previously a primarily cognitive specialty characterized by nontechmcal diagnostic methods and pharmacologic management, gastroenterology now is characterized increasingly by direct visual inspection, tissue sampling, and minimally invasive therapeutic intervention. Endoscopy can provide practical and costeffective therapy for many disorders that previously required more invasive surgical intervention. This article reviews the current status of gastrointestinal endoscopy. In particular, the focus is on developments that are likely to alter substantially the practice of gastroenterology in the near future. UPPER GASTROINTESTINAL ENDOSCOPY Diagnostic esophagogastroduodenoscopy (EGD) allows high-resolution visual inspection of the upper gastrointestinal tract from the esophagus to the second portion of the duodenum. Early endoscopes used fiberoptic bundles to transmit images to a small eyepiece attached to the external portion of the endoscope through which the endoscopist peered. The images were small and limited in resolution. Current instruments use small electronic chips (chargecoupled devices) that transmit an electronic signal to a video processor and display the image on high-resolution video monitors. The move toward electronic devices improved resolution, while allowing a reduction in endoscope diameter. The images now can be viewed by assisting nurses, which is of unquestionable value during complex therapeutic procedures. At most centers, endoscopic examinations are performed using topical anesthetics applied to the oropharynx in combination with intravenously administered sedatives. Sedation is provided primarily to relieve anxiety because upper From the Division of Gastroenterology, Hennepin County Medical Center, and University of Minnesota School of Medicine, Minneapolis, Minnesota (SM); and Stanford University School of Medicine; and Division of Gastroenterology, Stanford University Medical Center, Stanford, California (JVD)

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gastrointestinal endoscopy typically is not a painful procedure. The routine use of conscious sedation adds considerable cost to the procedure and is a contributing factor in a significant proportion of procedure-related complications. Expenses are incurred from a variety of sources ranging from the obvious (the cost of the sedative agents themselves) to often overlooked costs, such as lost work time for relatives or friends needed to escort the patient home after the procedure. In light of a desire to reduce cost, there is renewed interest in methods to eliminate the need for sedation without significantly compromising patient comfort. The development of ultrathin endoscopes may help achieve this goal. These new devices have outer diameters of 5.3 mm (compared with 9 mm for a typical diagnostic endoscope) and may be passed through the mouth or nose.zo,61 The transnasal route has been suggested to reduce gagging during instrument passage by eliminating elevation of the soft palate and taking a more direct approach to the posterior pharynx. These instruments have considerable potential in reducing the need for sedation. Upper gastrointestinal endoscopy can be used for a variety of indications. Among these are the diagnosis and management of patients with abdominal pain or upper gastrointestinal bleeding, the screening and diagnosis of esophagogastric malignancies, and the palliation of dysphagia resulting from malignant and benign causes.

Management of Bleeding Peptic Ulcers

Endoscopy is highly effective in identifying the site of acute upper gastrointestinal hemorrhage and in many cases allows therapeutic intervention not possible with radiographic imaging.68This ability not only to diagnose, but also to intervene therapeutically represented a major leap in the history of endoscopy. Approximately one half of acute upper gastrointestinal bleeding arises because of peptic ulcer disease. In general, endoscopic therapy is indicated in the setting of bleeding ulcers that possess certain high-risk features, such as the presence of ongoing active bleeding or a visible vessel within the ulcer base. In these instances, the application of electrocautery to the bleeding site, often in combination with local epinephrine injection, can reduce dramatically the risk of further hemorrhage, length of hospitalization, and overall mortality (Fig. l ) . I 5 Immediate hemostasis is possible in greater than 94% of cases, and this hemostasis persists in 80% to 85% of patients.68Even when rebleeding does occur, a large prospective trial suggests that a repeated attempt at endoscopic therapy often is effective and is associated with fewer complications than proceeding directly to Metallic clipping devices may enhance further the effectiveness of endoscopic therapy, especially in the setting of bleeding from large vessels or in patients with uncorrectable c~agulopathy.'~ Open surgical intervention for benign ulcer disease now is relatively uncommon; however, it remains an important adjunct to endoscopic therapy in the setting of persistent bleeding. Ulcers with certain features, such as active arterial bleeding, a visible vessel, an adherent clot, or size greater than 2 cm, are associated with higher rates of rebleeding30 Patients whose ulcers lack these stigmata are candidates for early discharge in the absence of other significant comorbid illness.38 In these instances, endoscopic evaluation may enhance significantly efforts to reduce treatment costs.

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Figure 1. Endoscopic hemostasis for peptic ulcer disease. A, A pulsatile jet of arterial blood is seen arising from the base of a gastric ulcer (beginning at the lower right hand corner of the image and extending to the upper left hand corner). 6, Immediate hemostasis is obtained following cautery using a 1OF bipolar cautery probe (seen extending from the endoscope at the lower right hand portion of the image).

Management of Variceal Bleeding

Acute variceal hemorrhage is associated with a 30% to 50% mortality.Injection sclerotherapy was considered to be the treatment of choice for actively bleeding esophageal varices, with initial hemostasis achievable in more than 90% of ~ases.2~ This techmque involves the injection of one or more of a variety .of proinflammatory and prothrombotic substances directly into a varix or into the immediate paravariceal region of the esophageal wall. Data regarding the efficacy of this modality continue to accumulate, documenting a reduction in resource use and improved hospital survival compared with untreated ~arices.2~ Side effects are not negligible, however, and include mucosal ulceration, stricture formation, bleeding, perforation, and, rarely, adult respiratory distress syndrome (ARDS). Since the initial reports in 1989,63variceal ligation technology has received increasing attention as a potentially superior therapeutic alternative to sclerotherapy (Fig. 2). It is becoming increasingly clear that ligation is superior to sclerotherapy for the management of active esophageal variceal hemorrhage, with less rebleeding, fewer local complications, and improved short-term surv i ~ a 1 Data . ~ ~ have suggested that ligation may be superior to therapy with p blockade for the primary prophylaxis of esophageal variceal h e m ~ r r h a g eThese .~~ data are in contrast to other data suggesting increased mortality with prophylactic ~clerotherapy.~~ Encouraging data have been published regarding variceal sclerotherapy using cyanoacrylate (superglue) and various other combinations of clotting factors or other agents." 51, 73 These substances appear to hold considerable promise, especially for the management of gastric varices (lesions much more refractory to endoscopic therapy than their esophageal counterparts); however, they are not currently approved for this indication in the United States.

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Figure 2. Endoscopic variceal band ligation (EVL) of an actively bleeding esophageal varix. A, A large variceal trunk is seen protruding into the midesophageal lumen. B, An active jet of nonpulsatile blood is seen arising from a varix at the gastroesophageal junction. C,Following variceal ligation the varix is seen as a rounded polypoid lesion protruding into the esophageal lumen. The black rubber band is seen at the base of the ligated portion of the varix. These three images were obtained from different patients.

Endoscopic Detection and Screening of Barrett’s Esophagus

The incidence of adenocarcinoma of the esophagus and gastric cardia is increasing more rapidly than that of any other cancer in the United States? This disease had accounted for only 10% of esophageal malignancies; however, it is now the eighth most prevalent cancer worldwide. The explanation for this epidemic remains obscure. In response to this disturbing trend, updated screening guidelines for Barrett’s esophagus were published by the American College of Gastr~enterology.~~ According to these guidelines, endoscopic evaluation is recommended for patients with a long-standing histoy of symptomatic gastroesophageal reflux, particularly in patients older than age 50. Approximately 8% to 20% of patients having these symptoms are found to have Barrett’s esophagus,

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and these patients have an approximately 0.5% to 1% annual incidence of adenocarcin~ma.~~ Once Barrett’s esophagus is identified, patients undergo serial endoscopic surveillance with multiple biopsies (e.g., 4 quadrants every 2 cm) every 1 to 2 years (Fig. 3). Esophageal resection is recommended when either malignancy or high-grade dysplasia is encountered. At present, there is no convincing evidence that the elimination of acid reflux by surgical or pharmacologic means alters the course of Barrett’s esophagus significantly. Methods for the endoscopic ablation of this tissue are being investigated; preliminary results do not yet warrant their use outside of experimental protocols.34,48 Self-Expanding Metallic Stents in the Management of Malignant Obstruction

Luminal obstruction arises commonly in the course of many gastrointestinal malignancies, particularly esophageal carcinoma, distal gastric carcinoma, pancreatic carcinoma, and colorectal carcinoma. Opinions vary widely among clinicians regarding the role of attempted curative surgical intervention for these patients. Even so, a large percentage of these patients are not candidates for attempted curative therapy (because of the presence of comorbid illness or an advanced stage at the time of diagnosis). In these patients, effective endoscopic palliation often can provide prompt symptomatic relief without the need for prolonged hospitalization. Esophageal endoprostheses were made of rigid material of a fixed diameter and were advanced forcibly through the stenosis.28,37 Self-expanding metallic

Figure 3. Barrett’s esophagus. A, A small tongue of Barren’s-type mucosa is seen in the center of the image. The darker mucosa towards the left of the image is similar in color to normal gastric mucosa (pink), in contrast to pale white mucosa of the esophagus. Barrett’s is suggested when the border between gastric and esophageal mucosa is seen proximal to the gastric rugal folds. In this case, the presence of a small white patch of residual esophageal mucosa below the sqaumocolumnarjunction (a “squamous island”) (center of image) is also suspicious. Diagnosis requires biopsy confirmation showing intestinal metaplasia. B, Biopsy forceps are used to obtain small mucosal samples. The forceps are shown opened in this image. They are then advanced against the mucosal surface and closed, pinching a small portion of mucosa which is removed for histologic analysis.

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stents (SEMS) have been developed for use in the gastrointestinal tract and biliary system. The devices are woven of a special metallic alloy that has the unique characteristic of being readily deformable but returning reliably to its original configuration when unstressed. These metallic devices can be compressed to a narrow diameter, advanced through a stenosis, then allowed to reexpand to achieve luminal patency. Many varieties of SEMS are available with nonpermeable plastic polymer or silicone coatings. These coated stents may be used to seal tracheoesophageal fistulas effectively (Fig. 4)., There are convincing data to suggest that SEMS are associated with fewer complications and shorter hospital stays than rigid endoprostheses in the treatment of malignant esophageal obstruction.28 The initial versions of SEMS employed delivery systems that were long enough only to reach approximately to the gastroesophageal junction. Longer deployment systems have been developed that allow placement in more distal portions of the gastrointestinal tract, however. Subsequently, encouraging results have been reported documenting efficacy for the management of malignant pyloric, duodenal, and colonic obstr~ction.~~, 62, 64 Intramuscular Botulinum Toxin for the Treatment of Achalasia

Botulinum toxins are the most potent poisons known, resulting in muscular paralysis by interfering with the release of acetylcholine or binding with the neurotransmitter in the presynaptic clefts. The endoscopic injection of botulinum toxin A into the lower esophageal sphincter has been shown to result in significant symptomatic improvement in many patients with a c h a l a ~ i aOnce . ~ ~ injected, the toxin inhibits muscular contraction of the lower esophageal sphincter, allowing improved esophageal emptying. Since the initial encouraging reports of this technique, it has become increasingly clear that the duration of relief in many patients is of only intermediate durati0n.4~Of patients, 40% to 50% develop recurrent symptoms within the first year after treatment. Given the propensity to symptomatic recurrence with botulinum toxin injection and the good long-term results and low morbidity reported with laparoscopic myotomy, botulinum toxin injection probably will be reserved for patients with high operative risk or contraindications to laparoscopy. NEW TECHNIQUES IN SELECTIVE TISSUE ABLATION Argon Plasma Coagulation

Traditional electrocautery requires direct contact between the cautery probe and the target tissue. This direct contact is at times difficult to obtain. Although laser therapy does not require contact, the energy beam cannot be directed tangentially to the long axis of the endoscope. Argon plasma coagulation (APC) is a novel technique that overcomes these limitations and allows noncontact, tangential tissue ablation. Using APC, the space between the target tissue and probe is filled with ionized argon gas. Electric energy in the form of a visible spark is transmitted by the gas to the tissue closest to the probe. APC appears to be less likely to produce transmural injury than standard methods of thermal ablation and is considerably less expensive to purchase than standard laser.27As such, APC may be especially useful in the treatment of bleeding lesions not

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associated with bowel wall thickening (e.g., arteriovenous malformations), in which there is risk of perforation with deep injury.I4 Photodynamic Therapy

Photodynamic therapy is a novel technique developed to provide highly selective ablation of neoplastic tissue, while sparing adjacent normal cells. Special pharmaceuticals called photosensitizers (which are typically porphyrin derivatives) are administered intravenously in a nontoxic form, selectively concentrated within neoplastic cells, then activated by laser light to become cytoto~ic.4~ Currently the use of photodynamic therapy is approved only for the palliation 36; however, numerous of obstructing esophageal and pulmonary malignan~ies~~, other applications are being in~estigated.~~ The only currently marketed photosensitizing agent (porfimer sodium) is not 100% selective for malignant cells. A clinically significant portion is deposited in skin, resulting in cutaneous photosensitivity. The tissue half-life of porfimer sodium is long, necessitating the avoidance of exposure to direct sunlight for 1 month. The development of newer agents with greater tumor specificity and shorter periods of cutaneous photosensitivity is likely in the near future. ENDOSCOPY OF THE SMALL INTESTINE (ENTEROSCOPY)

Standard upper gastrointestinal endoscopy is limited to the level of the second portion of the duodenum. Most lesions resulting in pain or acute hemorrhage are seen withn this proximal portion of the gastrointestinal tract, and standard diagnostic endoscopes were designed with t h s distance in mind. Routine visual inspection of the more distal small bowel (enteroscopy)is of low yield in most clinical situations and is neither cost-effective nor efficient. In specific circumstances, however, examination of more distal regions of the small ‘bowel may be necessary, and a variety of techniques have been developed for this purpose. The use of a pediatric colonoscope in place of a standard endoscope can reliably allow inspection distal to the ligament of Treitz. Two varieties of dedicated enteroscopes have been developed to allow examination of greater portions of the small bowel? Sonde enteroscopes are extremely long (400 cm) devices that are placed into the upper gastrointestinal tract, then allowed to advance into the distal small bowel by peristalsis. Examination is then performed during withdrawal of the device. This technique is limited because the endoscope cannot be readvanced, and only minimal therapeutic intervention is possible. Push enteroscopes are shorter (160 to 240 cm) and examine a smaller portion of the bowel. These devices, however, have the advantage of allowing controlled insertion and withdrawal. More importantly, specialized accessory devices allow directed biopsy or thermal ablation if significant lesions are found.66Inspection of the entire small bowel is accomplished reliably only by intraoperative endoscopy, during which the surgeon passes the endoscope manually through the surgically exposed When evaluating for sources of occult blood loss, enteroscopy traditionally has been reserved for use after negative colonoscopic and upper endoscopic evaluations. The yield of push-type enteroscopy in this setting is in the range of 60%.”12 A provocative study has suggested that such a policy of reserving enteroscopy for situations in which routine esophagogastroduodenoscopy is

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Figure 4. S e e legend on opposite page

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Figure 4. Treatment of esophagopulmonary fistula using a silicone-coated expandable metal endoprosthesis. A, An esophagopulmonaryfistula is seen by contrast esophagography. This patient developed persistent cough, fever, and dysphagia while undergoing radiation therapy for squamous cell carcinoma of the lung. Contrast is seen leaking from the esophageal lumen into the right lung, with little contrast proceeding into the more distal esophagus. 6, Endoscopic evaluation disclosed two fistulae in the mid-esophageal body. The true lumen of the esophagus is poorly seen in this image and is at the upper left corner. C, Immediately following placement of an expandable metal endoprosthesis, endoscopic examination from a similar location as in Figure 6 shows closure of the two fistulous openings. The narrow, striped guidewire is used to assist placement and removed following deployment. D, Contrast examination following deployment of the endoprosthesis shows flow of the contrast through the stent without leakage into the lung tumor cavity. An air-fluid level is seen within the pulmonary cavity, which required percutaneous drainage. The patient tolerated a mechanical soft diet and was discharged.

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negative may be inefficient. In this study of patients with documented iron deficiency and negative colonoscopic examinations, proceeding immediately to enteroscopy increased diagnostic yield from 41% to 67% (compared with standard esophagogastroduodenoscopy) and did so at lower cost." The most commonly identified source of bleeding identified in the small bowel during enteroscopy is a vascular ectasia (Fig. 5). Less common lesions include nonsteroidal anti-inflammatory drug-induced ulcers, diverticula, and a variety of benign or malignant tumors. COLONOSCOPY AND SIGMOIDOSCOPY Most significant technologic advances related to colonoscopy and sigmoidoscopy have been mentioned previously in the sections on upper endoscopy. These developments include the use of APC for superficial bleeding lesions (particularly arteriovenous malformations and radiation proctopathy in the co10n),I4the use of fnetallic clip devices for the management of postpolypectomy bleeding,65and the use of metallic stents for the palliation of malignant obstruct i ~ nAs . ~important ~ as these technologic advances have been, more progress has been made with regard to understanding of the indications for colonoscopy and in identifying rational strategies for the screening and surveillance of colorectal carcinoma. These data are reviewed briefly in the following section. Screening Sigmoidoscopy: Are All Adenomas Equal?

Advanced adenomatous polyps are defined as those with villous or tubulovillous histology, size greater than or equal to 1 cm, or regions of high-grade dysplasia. The detection of these polyps at screening sigmoidoscopy is known to correlate with an increased risk for the subsequent development of colorectal

Figure 5. Vascular ectasia (arteriovenous malformation, AVM). A collection of tortuous dilated vessels is seen in the center of this image consistent with an AVM. This lesion was seen in the cecum. Normal-sized colonic vessels are seen in the background.

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Figure 6. Colonoscopic polypectomy A, A large pedunculated polyp is seen at the center of the image attached by a narrow stalk to the colon wall at the upper right. 6,The same patient immediately following polypectomy.

cancer.' It generally is accepted that patients with advanced polyps at sigmoidoscopy warrant enrollment in a program of colonoscopic surveillance and polypectomy (Fig. 6). Many health care organizations, however, do not currently recommend colonoscopy for patients with small tubular (e.g., nonadvanced) adenomas found at sigmoidoscopy. Data from the Polyp Prevention Trial raised concerns regarding the appropriateness of such a policy.57In this study, 981 patients with distal adenomas found on initial colonoscopy were evaluated regarding the prevalence of concomitant proximal (e.g., beyond the reach of a sigmoidoscope) lesions. Patients with advanced distal lesions were twice as likely to have Concomitant advanced proximal lesions (5.9%versus 2.9%). A policy of reserving full colonoscopy for patients with advanced distal lesions would have failed to detect 36% of advanced proximal lesions, however. These data appear to support the performance colonoscopy for all patients with adenomatous polyps found at screening sigmoidoscopy, regardless of whether these polyps had advanced features. How Many Patients With Right-Sided Cancers Have Normal Sigmoidoscopic Examinations?

Previous data from retrospective studies have suggested that only a few patients with proximal cancers have polyps or cancers within reach of the A large prospective multicenter trial provided additional evisigmoido~cope.~~ dence?* Of 116 patients with proximal carcinomas, only 34.5%had a neoplastic lesion distal to the splenic flexure, and only 16% had distal adenomas greater than or equal to 1 cm. Most patients with carcinoma in this study would have had a normal sigmoidoscopy and would not have been referred for colonoscopy in a screening program based solely on sigmoidoscopy. It is admittedly not clear how many of these patients with proximal lesions would have been found to be occult-blood positive and referred for colonoscopy if occult blood testing also was performed. Data from the Minnesota Colon Cancer Control Study have

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shown that a program of annual stool testing can reduce colon cancer-related mortality by 33%.40

Potential Role of Screening Colonoscopy

The two studies discussed earlier show several potential limitations of screening programs based on sigmoidoscopy. As an alternative approach, guidelines have suggested that screening colonoscopy may be an acceptable Preliminary data from a Veteran’s Affairs Cooperative Study of screening colonoscopy suggest that screening colonoscopy generally is quite ~ a f e . 4The ~ greatest barrier to widespread acceptance of screening colonoscopy is the cost.

Alternatives to Diagnostic Colonoscopy

Considerable technologic improvements have occurred in the field of diagnostic radiology that mirror those of endoscopy. One particularly noteworthy 58 Virtual colonoscopy is a development is the introduction of virtual colonoscopy53~ unique method of reconstructing radiologically obtained (computed tomography [CT] or magnetic resonance [MR] imaging) high-resolution images to allow a video display that resembles the view seen inside the colon during colonoscopy. After computerized reconstruction, a radiologist (or gastroenterologist) can advance or withdraw electronically the virtual colonoscope through the colon searching for polyps or masses. This technique has the advantage of being less invasive than colonoscopy and eliminates the risk of perforation. One obvious disadvantage is the inability to biopsy, resect, or otherwise intervene when abnormalities are found. Mucosal inflammatory changes and angioectasia (see Fig. 5) are unlikely to be detected. At present, the sensitivity for polyps appears to be suboptimal, and virtual colonoscopy remains an investigational t001.5~This technology illustrates a prevailing and laudable goal in diagnostic and therapeutic imaging: to reserve invasive modalities for cases requiring therapeutic intervention.

PANCREATICOBILIARY ENDOSCOPY

Endoscopic retrograde cholangiopancreatography (ERCP) has become well established as a safe, effective method for the diagnosis and treatment of disorders of the biliary ductal system. Experience has shown several additional applications with regards to the pancreatic ductal system as we11.5 This procedure is performed using a specially designed endoscope, termed a duodenoscope, which images the lumen in a plane perpendicular to the long axis of the endoscope (side-viewing) rather than from the tip as with standard endoscopes (end-viewing). This duodenoscope allows visualization of the major and minor papillae en face and facilitates the insertion of devices into the desired duct. In the sections that follow, the current status of ERCP is reviewed with regards to the most common or the most rapidly evolving indications.

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Management of Retained Common Bile Duct Stones and Ascending Cholangitis

Using ERCP, the presence of stones can be assessed readily by the injection of contrast agents into the common bile duct? If stones are present, they can be removed at the same setting, providing prompt biliary drainage. If required, the bile duct opening may be enlarged by a sphincterotomy. In general, stones smaller than 1 cm diameter can be extracted after a sphincterotomy (Fig. 7): Larger stones may require fragmentation before removal. This fragmentation may be accomplished using mechanical crushing devices (lithotripters) or, more recently, electrohydrauliclithotripsy?*The latter generally is performed by bringing a small probe into contact with the stone, which emits a brief pulse of energy shattering the stone. This technique generally is performed under direct vision afforded by the use of ultrathin endoscopes (choledochoscopes), which can be advanced directly into the bile duct. Data suggest that ERCP is associated with lower rates of complications than surgical or transhepatic drainage?" ERCP is not without complications, however. When sphincterotomy is performed in the setting of suspected stone disease, approximately 3% of patients develop postprocedural pancreatitis.2zAlthough this pancreatitis typically is mild and self-limited, a small percentage is lifethreatening. ERCP should be reserved only for patients with known stones. As such, in experienced centers with low rates of unsuccessful cannulation, ERCP generally is performed before laparoscopic cholecystectomy only in situations of high suspicion of retained stones (e.g., the presence of jaundice, cholangitis, or visualized intraductal stones on ultrasound). Otherwise, potential choledocholithiasis can be assessed by intraoperative cholangiography, with endoscopic stone extraction performed postoperatively if needed. In patients not undergoing cholecystectomy imminently in whom the possibility of stone disease is raised but the index of suspicion is low to intermediate,

Figure 7. Endoscopic sphincterotomy. A, A specialized cannula (termed a papillotome) containing a bare wire is advanced into the biliary orifice. The wire is bowed and electrical current applied. 6, Continued application of cautery combined with careful advancement and/or further bowing of the papillotome produces an incision that enlarges the biliary orifice.

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alternate methods exist for the evaluation of the biliary tree. Endoscopic ultrasound (EUS) (described in a later section) is highly accurate and cost-effective in this situation and does not carry the associated risk of pancreatitis6 Imaging by MR cholangiopancreatography also is an option (Fig. €9, although it may be slightly less accurate than EUS.19 Few purely diagnostic ERCP studies should be performed, with stones being documented previously by less invasive examinations or the presence of obstruction based on clinical presentation. Management of Malignant Biliary Obstruction

Malignant biliary obstruction occurs most commonly as a result of pancreatic adenocarcinoma or cholangiocarcinoma. ERCP is often the first diagnostic step in the evaluation of these patients because it not only provides diagnostic information, but also allows the opportunity for palliation by the placement of biliary stents. The finding of a focal irregular biliary stricture is suspicious for carcinoma, particularly when accompanied by an adjacent stricture in the pancreatic duct (the so-called double-duct sign). When such a stricture is identified,

Figure 8. Magnetic resonance cholangiopancreatographyand endoscopic retrograde cholangiopancreatographyfor the detection of choledocholithiasis. A, MRCP. A patient with an unexplained episode of severe abdominal pain and gram-negative sepsis had no explanation found at exploratory laparotomy. Liver enzymes are abnormal; however, the patient had a history of alcohol-related liver disease. MRCP was obtained. The biliary tree is displayed as white structures. The large white circle in the middle of the image is the gallbladder, with the bile duct coursing to the right. A small stone is seen in the distal bile duct (arrow). B, ERCP in the same patient confirmed the presence of a small triangular stone (arrow), which was endoscopically removed. The duodenoscope is seen crossing from right to left, with a thin guidewire and cannula advanced into the duct.

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Figure 9. Endoscopically inserted plastic biliary stent. The distal tip is left protruding into the duodenal lumen.

tissue sampling can be performed by cytologic brushes, intraductal forceps, or cytologic aspiration needles. Despite aggressive attempts, however, the sensitivity of these techniques generally is reported to be less than 75%.26 Effective palliation of obstructive jaundice can be obtained by the insertion of a tent.^ Temporary stents are available that are made of plastic and resemble a drinking straw (Fig. 9). These stents have relatively narrow lumens (generally 5F to 12.5F) and are prone to occlusion. Average patency rates are approximately 3 to 4 months, at which point the stent must be endoscopically rep1a~ed.l~ Occlusion occurs typically as a result of tumor growth or infiltration with a biofilm containing bacteria and mucus. Alternatively a self-expandable metallic stent (as described previously) may be placed within the stricture (Fig. 10). These stents have the advantage of expanding to a larger luminal size and are associated with a longer duration of patency. Average patency rates for metallic stents are in the range of 9 months.17 These metallic stents are not readily removable and should be considered permanent. Occlusion may be managed by placing an additional plastic or metal stent within the occluded lumen. The use of metallic stents generally is discouraged in the absence of documented malignancy. Despite their greater initial cost, metallic stents generally are costeffective if the patient's life expectancy is greater than 3 to 4 months because of reduced need for repeat ERCP and hospitalizations for Management of Benign Biliary Obstruction

Benign biliary obstruction may arise because of primary sclerosing cholangitis or in response to previous surgical manipulation. Depending on the clinical situation, it may be difficult to differentiate benign from malignant strictures. In these situations, choledochoscopy or endoscopic ultrasonography may be of use? Benign strictures may be treated endoscopically by repeated dilation (using progressively larger-diameter tapered rigid catheters or balloons) with the placement of temporary stents over the course of several months. The overall success

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Figure 10. Endoscopically inserted expandable metallic biliary stent. This image shows the lumen of the bile duct as seen from the duodenum.

rate is approximately 75%, which approaches that of surgical intervention.I8The duration of treatment is greater than the relatively prompt results seen with surgical management, however.

Predictors of Endoscopic Retrograde Cholangiopancreatography-Related Complications The preponderance of significant advances relating to ERCP has been in outcomes research. Several studies have enhanced the understanding of factors contributing to ERCP-related complications, and this understanding should lead 25 Although to a reduction in complications and improved generally safe, ERCP is an invasive technology that carries the risk of significant and fatal complications. The most common complications include pancreatitis, bleeding, perforation, and infection, with mortality being rare but not impossible. Predictors of these complications had not been well understood; however, a large-scale multicenter prospective cohort study evaluated numerous proposed risk factors for complications of sphincterotomy and identified the following as independently significant: suspected sphincter of Oddi dysfunction, cirrhosis, difficult bile duct cannulation, the use of precut (access) sphincterotomy, and the use of combined percutaneous and endoscopic techniques.= Of these, the presence of suspected sphincter of Oddi dysfunction and cirrhosis are identified readily before the examination. Sphincter of Oddi dysfunction is a poorly understood disorder characterized by idiopathic biliary-type or pancreatic-type abdominal pain thought to arise as a result of overly vigorous contraction of the sphincter of Oddi. The decision to perform ERCP must be considered carefully because the risk of pancreatitis in this setting may be 20Y0.~~

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ENDOSCOPIC ULTRASONOGRAPHY

EUS represents perhaps the most clinically significant technologic advance in endoscopy during the past 10 years? Standard transcutaneous ultrasound is limited in its ability to image the retroperitoneum and distal common bile duct adequately because of interference from intervening air-filled structures. Ultrasound also has been of limited utility in the chest and mediastinum because of interference from the bony thorax and air-filled lungs. Placement of the transducer within the body allows many of these interfering structures to be avoided and provides remarkably detailed imaging of the distal common bile duct, pancreas, and mediastinal structures. An additional benefit of EUS is the ability to use higher-frequency sound, providing greater image resolution. Transabdominal ultrasound typically uses frequencies in the range of 3.5 MHz to allow imaging of deep structures, whereas EUS can use sound frequencies of 20 MHz. At 20 MHz, the luminal gastrointestinal tract wall may be imaged as nine distinct layers that correlate closely with histology (Fig. 11).This level of resolution is, at present, unique to EUS and is of particular value in the preoperative staging of gastrointestinal malignancies and the evaluation of intramural submucosal masses. In addition to providing high-resolution imaging, diagnostic tissue sampling can be performed readily by EUS, and several therapeutic applications have been reported. Endoscopic Ultrasonographyfor the Diagnosis and Staging of Pancreatic Cancer

EUS provides highly detailed imaging of the pancreas. The sensitivity of EUS for the identification of focal mass lesions generally has been reported to be superior to that of CT scanning, particularly for small (<3 cm diameter)

Figure 11. High resolution (20 MHz) endoscopic ultrasound image of the normal esophagus. A, Ultrasound image showing the esophageal wall as a 9-layered structure (AzV = azygous vein, TD = thoracic duct). B, Magnified image of the region within white box on Figure A. Hyperechoic (bright) layers are labeled with white numerals, hypoechoic (dark) layers with black numerals.

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tum0rs.4~Studies comparing EUS with newer spiral CT techniques continue to favor EUS.41In addition to simply identifying the mass lesion, the identification of vascular invasion (a key determinant in evaluating surgical resectability) is possible by EUS, with an accuracy of 80% to 90% (similar to that of CT scanning 5, 41 or angi~graphy).~, A major advance in EUS in the 1990s has been the refinement of techniques for EUS-guided tissue sampling (Fig. 12). Diagnostic needle aspiration can be performed with little risk and provides an accurate tissue diagnosis in approxi~ , ~ technique is useful in identifying the approximately mately 85% of c a ~ e s .This 10% of focal mass lesions that arise as a result of causes other than primary ductal carcinoma. The primary limitation of this technique is related to difficulty in confidently excluding a malignancy in the presence of focal chronic pancreatitis, the appearance of which may mimic a neoplasm. EUS is of particular use in the evaluation of several less common pancreatic malignancies. The ability of EUS to localize pancreatic islet cell tumors has been well established and compares favorably with that of somatostatin ~cintigraphy.~~ EUS is less able to identify intraduodenal or intrahepatic tumors, and scintigraphy (which is less invasive) generally is considered the test of first choice. An exception to this rule is the evaluation of insulinoma, for which EUS is significantly superior to s~intigraphy.~~ Cystic pancreatic neoplasms account for approximately 10% of pancreatic cystic lesions and are relevant in that they are highly curable. Although a significant percentage of these neoplasms are considered malignant, the overall prognosis, if accurately identified and resected, is outstanding. In this situation, EUS-guided needle aspiration can provide an accurate preoperative diagnosi~.~

Figure 12. Diagnostic needle aspiration of a small pancreatic adenocarcinoma. The patient presented with abdominal pain. CT scan suggested possible fullness in the pancreatic head but without a discrete mass. A, EUS shows a hypoechoic mass measuring 22 x 17 mrn in diameter without involvement of the portal vein. The three white arrows indicate the borders of the mass. B, Needle aspiration confirmed adenocarcinoma. The 22 gauge needle is seen as a bright hyperechoic line entering the mass from the upper right hand corner. The arrow indicates the needle tip.

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Endoscopic Ultrasonography-Guided Celiac Neurolysis

Many patients with pancreatic ductal adenocarcinoma are technically unresectable at the time of diagnosis (because of the presence of metastases, vascular invasion, or prohibitive comorbid illness). In these patients, the clinical focus changes from potential cure to effective palliation. Although classically taught as causing painless jaundice, pancreatic carcinoma often results in abdominal pain, which can be quite debilitating. This pain has responded well to percutaneous celiac plexus neurolysis, and the ability to perform effective celiac neurolysis by EUS is a logical goal. The celiac trunk is readily visualized endosonographically directly posterior to the gastric wall. Although the celiac ganglia are not visualized directly by EUS (or any other imaging modality), they are reliably located adjacent to this vascular trunk. This site is readily amenable to needle puncture by EUS because the needle path required is short (1 to 2 cm)and generally free of intervening structures. A variety of substances may be injected, depending on the clinical situation. In general, celiac plexus block adds less than 5 minutes to the examination time. Data suggest that EUS-guided celiac block is safe and provides effective, long-lasting pain relief for most patients with pain resulting from malignan~y.~~ This is an important new development and enhances greatly the clinical value of EUS. In a single setting, EUS can provide accurate diagnosis, staging, and palliation for patients with unresectable pancreatic cancer. Early studies suggest that EUS-guided celiac block may provide effective pain relief for some patients with chronic pancreatitis, although the frequency of effective relief is lower than that for malignant indications, and the relief rarely persists for greater than 6 rn0nths.2~

Evolving Role of Endoscopic Ultrasonography in Esophageal Cancer

Esophageal cancer staging according to the most conmonly accepted (TNM) classification system is determined by the depth of penetration of neoplastic cells through the esophageal wall (T) and the presence or absence of nodal (N) or distant metastases (M). Along with the degree of comorbid illness, the stage of disease at presentation is one of the most accurate predictors of clinical outcome and traditionally has been important in determining optimal treatment. EUS is the only currently available imaging technology that allows the visualization of the distinct histologic tissue layers of the esophageal wall. As such, EUS is uniquely suited to the staging of esophageal malignancies (Fig. 13). Reported staging accuracy rates generally have been far superior with EUS compared with other imaging m ~ d a l i t i e s . ~ ~ Accurate preoperative staging is useful only if this information influences therapeutic decision making. Data showed convincingly that patients with T4 tumors by preoperative EUS do not benefit from attempted surgical resection as a sole means of treatment9 These data were obtained before the widespread use of neoadjuvant (preoperative) chemoradiation therapy. An evaluation of the outcomes of patients receiving neoadjuvant therapy showed that the presence of T4 disease (i.e., an advanced tumor involving an adjacent structure or organ) at pretreatment EUS does not preclude a complete pathologic response.39The likellhood of a complete response was unaffected by the presence or absence of

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Figure 13. Endoscopic ultrasound of esophageal carcinoma. The mass is seen as hypoechoic thickening of the wall. No wall layers are visualized indicating at least a T2 lesion. At the lower left, the outer borders of the esophagus are irregular (labeled THROUGH), indicating extension of the mass into the adventitia (T3 disease).There is an intact interface between the mass and the aorta, suggesting a lack of invasion into this structure.

nodal metastases. It remains to be determined whether long-term survival correlates with initial EUS stage. The exact role of EUS in the evaluation of esophageal carcinomas has yet to be determined. At present, if neoadjuvant therapy is not being considered (because of contraindications or the physician’s opinion regarding the effectiveness of this therapy), EUS staging is useful and should be considered if initial evaluation with CT scans of the chest and abdomen fail to show metastatic disease. Current data suggest that patients with T4 tumors might be treated best nonoperatively. If neoadjuvant therapy is planned, treatment decisions (at present) currently should not be based on the results of EUS, unless distant metastases are found. EUS remains a valuable part of experimental protocols because it provides the most accurate assessment of initial severity of disease for the purposes of comparing the results of clinical trials. Evaluation of Suspected Choledocholithiasis

Neither transabdominal ultrasonography nor CT scanning can exclude reliably the presence of choledocholithiasis.ERCP is highly accurate for this diagnosis but is associated with a risk of pancreatitis and would be reserved for patients with known common duct stones. Data have shown that EUS is approximately equivalent to ERCP with regards to sensitivity and overall accuracy for the detection of common duct stones, and the risk of pancreatitis is negligible? EUS was also shown to be more cost-effective than ERCP for patients with low to intermediate likelihood of stones. The sensitivity and accuracy of EUS and MRCP appear to be equivalent in evaluating patients with suspected common bile duct stones.l9 EUS is more portable than ERCP or MRCP and useful for

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patients in the intensive care unit. EUS (if performed in the fluoroscopy suite) can be followed immediately by therapeutic ERCP, saving time. At this time, the choice between EUS and MRCP is determined best on a case-by-case basis. Additional Applications of Endoscopic Ultrasonography

One of the first reported uses of EUS was in the evaluation of subepithelial tumors of the gastrointestinal tract. Some mass lesions exist within the wall of the gastrointestinal tract but are covered by a layer of normal epithelium which, in general, prevents diagnostic tissue sampling with standard endoscopic biopsy. By using EUS, determination of the layer of origin and echogenicity of these lesions can narrow significantly the differential diagnosis. Certain sonographic characteristics have been studied that appear to allow identification of a subset of lesions that warrant surgical resection.l0 Needle aspiration cytology can be useful in obtaining a definitive tissue diagnosis. Several centers have suggested that EUS may be useful in the evaluation of suspected chronic pancreatitis.7,54 EUS correlates highly with other imaging studies in the setting of severe disease. A subset of patients with chronic pain syndromes have similar EUS findings despite a lack of abnormalities by CT scanning or ERCP. It has been suggested that these patients also may have chronic pancreatitis and that EUS is more sensitive and specific for this diagnosis; however, it is not yet clear whether all of these patients actually have disease because a gold standard for this diagnosis (e.g., histologic analysis) rarely is available. SUMMARY

Endoscopy is extremely valuable in the evaluation of disorders of the luminal gastrointestinal tract, pancreas, and biliary system. Endoscopy as a medical discipline continues to evolve and is becoming increasingly therapeutic in nature. Minimally invasive endoscopic intervention now is effective in a wide variety of disorders, including gastrointestinal hemorrhage, obstructive diseases of the intestinal or biliary tree, and early detection or prevention of neoplastic disease of the colon and esophagus. The development of EUS technology has expanded greatly the potential utility of endoscopy as a diagnostic and a therapeutic modality, and further technologic advances are anticipated. References 1. Atkin WS, Morson BC, Cuzick J: Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 326:658-662, 1992 2. Bemer JS, Mauer K, Lewis BS: Push and sonde enteroscopy for the diagnosis of obscure gastrointestinal bleeding. Am J Gastroenterol 892139-2142, 1994 3. Blot WJ, Devesa SS, Kneller RW, et al: Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287-1289, 1991 4. Brugge W R Endoscopic ultrasonography: The current status. Gastroenterology 115:1577-1583. 1998 5. Brugge WR, Van Dam J: Pancreatic and biliary endoscopy. N Engl J Med 341:18081816, 1999

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6. Canto MIF, Chak A, Stellato T, et al: Endoscopic ultrasonography versus cholangiography for the diagnosis of choledocholithiasis. Gastrointest Endosc 47439448, 1998 7. Catalan0 MF, Lahoti S, Geenen JE, et al: Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 48:ll-17, 1998 8. Cave DR, Cooley JS: Intraoperative endoscopy: Indications and techniques. Gastrointest Endosc Clin N Am 6:793-802, 1996 9. Chak A, Canto M, Gerdes H, et al: Prognosis of esophageal cancers preoperatively staged to be locally invasive (T4) by endoscopic ultrasound (EUS): A multicenter retrospective cohort study. Gastrointest Endosc 42:501-506, 1995 10. Chak A, Canto MI, Rosch T, et al: Endosonographic differentiation of benign and malignant stromal cell tumors. Gastrointest Endosc 45:468-473, 1997 11. Chak A, Cooper GS, Canto MI, et al: Enteroscopy for the initial evaluation of iron deficiency. Gastrointest Endosc 47144-148, 1998 12. Chong J, Tagle J, Barkin JS, et al: Small bowel push type enteroscopy for patients with occult gastrointestinal bleeding of suspected small bowel pathology. Am J Gastroenterol 89:2143-2146, 1994 13. Chung I-K, Ham J-S, Kim H-S, et al: Comparison of the hemostatic efficacy of the endoscopic hemoclip method with hypertonic saline-epinephrine injection and a combination of the two for the management of bleeding peptic ulcers. Gastrointest Endosc 49:13-18, 1999 14. Cohen J, Abedi M, Haber G, et al: Argon plasma coagulation: A new effective technique of non-contact thermal coagulation: Experience in 44 cases of GI angiomata [abstr]. Gastrointest Endosc 43:293, 1996 15. Cook DJ, Guyatt GH, Salena BJ, et al: Endoscopic therapy for acute nonvariceal upper gastrointestinal hemorrhage: A meta-analysis. Gastroenterology 102:139-148, 1992 16. Craig A, Hanlon J, Dent J, et al: A comparison of transnasal and transoral endoscopy with small-diameter endoscopes in unsedated patients. Gastrointest Endosc 49:292296, 1999 17. Davids PH, Groen AK, Rauws EA, et al: Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant obstruction. Lancet 340:14881492, 1992 18. Davids PH, Tanka AK, Rauws EA, et al: Benign biliary strictures: Surgery or endoscopy? Ann Surg 217:237-243, 1993 19. de Ledinghen V, Lecesne R, Raymond J-M, et al: Diagnosis of choledocholithiasis: EUS or magnetic resonance cholangiography? A prospective controlled study. Gastrointest Endosc 49:26-31, 1999 20. Dumortier J, Ponchon T, Scoazec J-Y, et al: Prospective evaluation of transnasal esophagogastroduodenoscopy: Feasibility and study on performance and tolerance. Gastrointest Endosc 49:285291, 1999 21. Freeman ML, Nelson DB, Sherman S, et al: Same-day discharge after endoscopic biliary sphincterotomy: Observations from a prospective multicenter complication study. Gastrointest Endosc 49:580-586, 1999 22. Freeman ML, Nelson DB, Sherman S, et al: Complications of endoscopic biliary sphincterotomy. N Engl J Med 335:909-918, 1996 23. Gress F, Schmitt C, Sherman S, et al: A prospective randomized comparison of endoscopic ultrasound- and computed tomography-guided celiac plexus block for managing chronic pancreatitis pain. Am J Gastroenterol 94:900-905, 1999 24. Hartigan I'M, Gebhard RL, Gregory PB: Sclerotherapy for actively bleeding esophageal varices in male alcoholics with cirrhosis. Veterans Affairs Cooperative Variceal Sclerotherapy Group. Gastrointest Endosc 46:l-7, 1997 25. Ho KY, Montes H, Sossenheimer MJ, et al: Features that may predict hospital admission following outpatient therapeutic ERCP. Gastrointest Endosc 49:587-592, 1999 26. Howell DA, Beveridge RP, Bosco J, et al: Endoscopic needle aspiration biopsy at ERCP in the diagnosis of biliary strictures. Gastrointest Endosc 38:531-535, 1992 27. Johanns W, Luis W, Janssen J, et al: Argon plasma coagulation (APC) in gastroenterology: Experimental and clinical experiences. Eur J Gastroenterol Hepatol9:581-587,1997 28. Knyrim K, Wagner H-J, Bethge N, et al: A controlled trial of an expansile metal stent

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for palliation of esophageal obstruction due to inoperable cancer. N Engl J Med 329~1302-1307,1993 29. Laine L, Cook D: Endoscopic ligation compared with sclerotherapy for the treatment of esophageal variceal bleeding: A meta analysis. AM Intern Med 123:280-287, 1995 30. Laine L, Peterson WL: Bleeding peptic ulcer. N Engl J Med 331:717-727, 1994 31. Lau JYW, Sung JJY, Lam Y-H, et al: Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 340:751-756, 1999 Endoscopic management of difficult common bile duct stones. 32. Lee JG, Leung JW: Gastrointest Endosc Clin N Am 6:43-55, 1996 33. Lemmel GT, Haseman JH, Rex DK, et al: Neoplasia distal to the splenic flexure in patients with proximal colon cancer. Gastrointest Endosc 44:109-111, 1996 34. Lightdale CJ: Ablation therapy for Barrett’s esophagus: Is it time to choose our weapons? Gastrointest Endosc 49:122-125, 1999 35. Lightdale CJ, Heier SK, Marcon NE, et al: Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: A multicenter randomized trial. Gastrointest Endosc 42507-512, 1995 36. Likier HM, Levine JG, Lightdale CJ: Photodynamic therapy for completely obstructing esophageal carcinoma. Gastrointest Endosc 3775-78, 1991 37. Loizou LA, Grigg D, Atkinson M, et al: A prospective comparison of laser therapy and intubation in endoscopic palliation for malignant dysphagia. Gastroenterology 1001303-1310, 1991 38. Longstreth GF, Feitelberg SP: Successful outpatient management of acute upper gastrointestinal hemorrhage: Use of practical guidelines in a large patient series. Gastrointest Endosc 47219-222, 1998 39. Mallery S, Decamp M, Bueno R, et al: Pretreatment staging by endoscopic ultrasonography does not predict complete response to neoadjuvant chemoradiation in patients with esophageal carcinoma. Cancer 86:764-769, 1999 40. Mandel JS, Bond JH, Church TR, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 328~1365-1371, 1993 41. Midwinter MJ, Beveridge CJ, Wilsdon JB, et al: Correlation between spiral computed tomography, endoscopic ultrasonography and findings at operation in pancreatic and ampullary tumors. Br J Surg 86:189-193, 1999 42. Miyazaki S, Yoshida T, Harada T, et al: Injection sclerotherapy for gastric varices using N-butyl-2-cyanoacrylate and ethanolamine oleate. Hepatogastroenterology 45:11551158, 1998 43. Muller MF, Meyenberger C, Bertschinger P, et al: Pancreatic tumors: Evaluation with endoscopic US, CT, and MR imaging. Radiology 190:745-751, 1994 44. Nelson DB, Axelrod AM, Fleischer DE, et al: Silicone-covered Wallstent prototypes for palliation of malignant esophageal obstruction and digestive-respiratory fistulas. Gastrointest Endosc 45:31-37, 1997 45. Nelson DB, McQuaid KR, Bond JH, et al: Population-based colonoscopy screening for colorectal cancer is feasible and safe: Preliminary results from the VA Colonoscopy Screening Trial [abstr]. Gastrointest Endosc 49:AB65, 1999 46. Nevitt AW, Vida F, Kozarek RA, et al: Expandable metallic prostheses for malignant obstructions of gastric outlet and proximal small bowel. Gastrointest Endosc 47271276, 1998 47. Nishioka N: Drug, light and oxygen: A dynamic combination in the clinic. Gastroenterology 114604406, 1998 48. Overholt BF, Panjepour M, Haydek JM: Photodynamic therapy for Barrett’s esophagus: Follow-up in 100 patients. Gastrointest Endosc 49:l-7, 1998 49. Pasricha PJ, Rai R, Ravich WJ, et al: Botulinum toxin for achalasia: Long term outcome and predictors of response. Gastroenterology 110:141(n415, 1996 50. Pasricha PJ, Ravich WJ, Hendrix TR, et al: Treatment of achalasia with intrasphincteric injection of botulinum toxin-a pilot trial. Ann Intern Med 121:590-591, 1994

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51. Przemioslo RT, McNair A, Williams R Thrombin is effective in arresting bleeding from gastric variceal hemorrhage. Dig Dis Sci 44:778-781, 1999 52. Rex DK, Chak A, Vasudeva R, et al: Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Gastrointest Endosc 49:727-730, 1999 53. Rex DK, Vining D, Kopecky K K An initial experience with screening for colon polyps using spiral CT with and without CT colography. Gastrointest Endosc 50:309-313, 1999 54. Sahai AV, Zimmerman M, Aabakken L, et al: Prospective assessment of the ability of endoscouic ultrasound to diamose. " . exclude, or establish the severitv of chronic uancreatitis foind by endoscopic retrograde cholangiopancreatography. Gastrointest 'Endosc 48:18-25, 1998 55. Sampliner R Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 93:1028-1032, 1998 56. Sarin SK, Lamba GS, Kumar M, et al: Comparison of endoscopic ligation and propranolo1 for the primary prevention of variceal bleeding. N Engl J Med 340:988-993, 1999 57. Schoen RE, Corle D, Cranston L, et al: Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy? Gastroenterology 115:533-541, 1998 58. Schoenenberger AW, Bauerfeind , ' l Krestin GP, et al: Virtual colonoscopy with magnetic resonance imaging: In vitro evaluation of a new concept. Gastroenterology 112:18631870, 1997 59. Sibille A, Lambert R, Souquet J-C, et al: Long-term survival after photodynamic therapy for esophageal cancer. Gastroenterology 1083337-344, 1995 60. Siege1 JH, Rodriguez R, Cohen SA, et al: Endoscopic management of cholangitis: Critical review of an alternative technique and report of a large series. Am J Gastroenterol 89:1142-1146, 1994 61. Sivak MV Jr: The nose: Is this the route to improving esophagogastroduodenoscopy? Gastrointest Endosc 49:395-398, 1999 62. Soetikno RM, Lichtenstein DR, Vandervoort J, et al: Palliation of malignant gastric outlet obstruction using an endoscopically placed wallstent. Gastrointest Endosc 47267-270, 1998 63. Stiegmann GV, Goff JS, Sun JH, et al: Endoscopic elastic band ligation for active variceal hemorrhage. Am Surg 553124-128, 1989 64. Tack J, Gevers A-M, Rutgeerts I? Self-expandable metallic stents in the palliation of rectosigmoid carcinoma: A follow-up study. Gastrointest Endosc 48:267-271, 1998 65. Uno Y, Satoh K, Tuji K, et al: Endoscopic ligation by means of clip and detachable snare for management of colonic post-polypectomy hemorrhage. Gastrointest Endosc 49:113-115, 1999 66. Vakil N, Huilgol V, Khan I: Effect of push enteroscopy on transfusion requirements and quality of life in patients with unexplained gastrointestinal bleeding. Am J Gastroenterol 92:425-428, 1997 67. Van Dam J: Endosonographic evaluation of the patient with esophageal cancer. Chest 112:184S-l9OS, 1997 68. Van Dam J, Brugge W R Endoscopy of the upper gastrointestinal tract. N Engl J Med 341:1738-1748, 1999 69. Veterans Affairs Cooperative Variceal Sclerotherapy Group: Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease: A randomized, single-blind, multicenter clinical trial. N Engl J Med 324:1779-1784, 1991 70. Wiersema MJ, Wiersema L M Endosonography-guided celiac plexus neurolysis. Gastrointest Endosc 44~656462,1996 71. Winawer SJ, Fletcher RH, Miller L, et al: Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 1123594-642, 1997 72. Yeoh KG, Zimmerman MJ, Cunningham JT, et al: Comparative costs of metal versus plastic biliary stent strategies for malignant obstructive jaundice by decision analysis. Gastrointest Endosc 49:466471, 1999 73. Zimmer T, Rucktaschel F, Stolzel U, et al: Endoscopic sclerotherapy with fibrin glue as

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compared with polidocanol to prevent early esophageal variceal rebleeding. J Hepatol 28:292-297, 1998 74. Zimmer T, Stolzel U, Bader M, et al: Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas. Gut 39~562-568,1996 Address reprint requests to Jacques Van Dam, MD, PhD Division of Gastroenterology Stanford University Medical Center 300 Pasteur Drive, Room H1121 Stanford, CA 94305-5202