Robert H. Hawes

Radiofrequency Ablation in Barrett's Esophagus with Dysplasia

BACKGROUND Barretts esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barretts esophagus and decrease the rate of neoplastic progression. METHODS In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barretts esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barretts esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS In patients with dysplastic Barretts esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

Endoscopic ultrasound guided fine needle aspiration biopsy: a large single centre experience

BACKGROUND Endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) is a recent innovation in the evaluation of gastrointestinal and pulmonary malignancies. AIMS To review the experience with EUS-FNA of a large single centre. METHODS 333 consecutive patients underwent EUS-FNA. Follow up data were available on 327 lesions in 317 patients, including 160 lymph nodes, 144 pancreatic lesions, 15 extraintestinal masses, and eight intramural tumours. RESULTS A primary diagnosis of malignancy was obtained by EUS-FNA in 62% of patients with clinically suspicious lesions. The overall accuracy of EUS-FNA for the diagnosis of malignancy was 86%, with sensitivity of 84% and specificity of 96%. With respect to lesion types, the sensitivity, specificity, and accuracy were 85%, 100%, and 89% for lymph nodes; 82%, 100%, and 85% for pancreatic lesions; 88%, 100%, and 90% for perirectal masses; and 50%, 25%, and 38% for intramural lesions, respectively. Compared with size and sonographic criteria, EUS-FNA in the evaluation of lymph nodes provided superior accuracy and specificity, without compromising sensitivity. Inadequate specimens were obtained from only six patients, including 3/5 with stromal tumors. Only one complication occurred. CONCLUSIONS EUS-FNA is safe and can readily obtain tissue specimens adequate for cytopathological diagnoses. Compared with size and sonographic criteria, it is a superior modality for the detection of nodal metastases. While providing accurate diagnosis of pancreatic and perirectal malignancies, results suggest the technique is less useful for intramural lesions.

Endoscopic gastrojejunostomy with survival in a porcine model

BACKGROUND We have previously reported the feasibility and the safety of an endoscopic transgastric approach to the peritoneal cavity in a porcine model. We now report successful performance of endoscopic gastrojejunostomy with survival. METHODS All procedures were performed on 50-kg pigs, with the pigs under general anesthesia, in aseptic conditions with sterilized endoscopes and accessories. The stomach was irrigated with antibiotic solution, and a gastric incision was performed with a needle-knife and a sphincterotome. A standard upper endoscope was advanced through a sterile overtube into the peritoneal cavity. A loop of jejunum was identified, was retracted into the stomach, and was secured with sutures while using a prototype endoscopic suturing device. An incision was made into the jejunal loop with a needle-knife, and the filet-opened ends of the jejunal wall were secured to the gastric wall with a second line of sutures, completing the gastrojejunostomy. OBSERVATIONS Two pigs survived for 2 weeks. Endoscopy and a radiographic contrast study performed after gastrojejunostomy revealed a patent anastomosis with normal-appearing gastric and jejunal mucosa. Postmortem examination demonstrated a well-healed anastomosis without infection or adhesions. CONCLUSIONS The endoscopic transgastric approach to create a gastrojejunostomy is technically feasible and can be performed, with survival, in a porcine model.

Endoscopic ultrasound–guided fine-needle aspiration biopsy using linear array and radial scanning endosonography

BACKGROUND Endoscopic ultrasound (EUS) accurately stages gastrointestinal malignancies but is less able to differentiate between neoplastic and inflammatory processes. EUS-guided fine-needle aspiration (EUS FNA) has been reported useful for obtaining a diagnosis in suspected gastrointestinal lesions. We report our entire experience with EUS FNA using both radial and linear array endosonography, including our diagnostic accuracy and complication rate. METHODS Two hundred eight consecutive patients (119 men, 89 women) referred for EUS evaluation of suspected gastrointestinal or mediastinal masses underwent EUS-guided FNA. We performed EUS FNA using radial scanning or linear array endosonography and a 23 gauge, 4 cm needle or a 22 gauge, 12 cm needle. Data collected included lesion types, number of passes, complications, and diagnostic accuracy. RESULTS Two hundred eight lesions were targeted, with a total of 705 FNA passes (mean 3.39 passes/patient). Overall diagnostic accuracy for our study population was 87% with a 89% sensitivity and 100% specificity. The diagnostic accuracy for each subgroup was 95% for mediastinal lymph node, 85% for intra-abdominal lymph node, 85% for pancreatic, 84% for submucosal, and 100% for perirectal masses. EUS FNA provided an adequate specimen in 90% of patients. The FNA results were similar for both types of endosonography. We observed immediate complications in 2% (4 of 208) of patients. All complications occurred with EUS FNA of pancreatic lesions and consisted of bleeding and pancreatitis in 2 patients each. For EUS FNA of pancreatic masses there was a 1.2% (2 of 121) risk of pancreatitis, 1% (1/121) risk of severe bleeding, and risk of death in less than 1%. CONCLUSIONS EUS-guided FNA appears to be technically feasible, safe, and accurate for obtaining diagnostic tissue of suspicious gastrointestinal and mediastinal lesions and provides important preoperative information.

Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction

BACKGROUND & AIMS Patients with sphincter of Oddi dysfunction are at high risk of developing pancreatitis after endoscopic biliary sphincterotomy. Impaired pancreatic drainage caused by pancreatic sphincter hypertension is the likely explanation for this increased risk. A prospective, randomized controlled trial was conducted to determine if ductal drainage with pancreatic stenting protects against pancreatitis after biliary sphincterotomy in patients with pancreatic sphincter hypertension. METHODS Eligible patients with pancreatic sphincter hypertension were randomized to groups with pancreatic duct stents (n = 41) or no stents (n = 39) after biliary sphincterotomy. The primary measured outcome was pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). RESULTS Pancreatic stenting significantly decreased the risk of pancreatitis from 26% to 7% (10 of 39 in the no stent group and 3 of 41 in the stent group; P = 0.03). Only 1 patient in the stent group developed pancreatitis after sphincterotomy, and 2 others developed pancreatitis at the time of stent extraction. Patients in the no stent group were 10 times more likely to develop pancreatitis immediately after sphincterotomy than those in the stent group (relative risk, 10.5; 95% confidence interval, 1.4-78.3). CONCLUSIONS Pancreatic duct stenting protects significantly against post-ERCP pancreatitis in patients with pancreatic sphincter hypertension undergoing biliary sphincterotomy. Stenting of the pancreatic duct should be strongly considered after biliary sphincterotomy for sphincter of Oddi dysfunction; pancreatic sphincter of Oddi manometry identifies which high-risk patients may benefit from pancreatic stenting.

A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion.

BACKGROUND The purpose of this study was to re-evaluate echo features of lymph nodes during endoscopic ultrasound and assess the utility of these echo features and endoscopic ultrasound-guided fine-needle aspiration in predicting malignant lymph node invasion. METHODS Thirty-five lymph nodes in 25 patients with lung, esophageal, and pancreatic cancer were evaluated by endoscopic ultrasound. Endoscopic ultrasound examinations were performed with a radial scanning echoendoscope. Confirmation of benign lymph nodes was obtained by surgical resection while malignant lymph nodes were confirmed by real-time endoscopic ultrasound-guided fine-needle aspiration with a linear array echoendoscope. RESULTS Nineteen benign lymph nodes and 16 malignant lymph nodes in the mediastinum, celiac axis, and the peripancreatic area were included in the study. The following echo features were compared between benign and malignant lymph nodes: size greater than 1 cm, hypoechoic, distinct margins, and round shape. No single feature independently predicted malignant invasion. When all four of the above features were present in the same lymph node, the accuracy for predicting malignant invasion was 80%. However, all four features of malignant involvement were present in only 25% (4 of 16) of malignant lymph nodes. Our study also suggests that the above echo features may be a less reliable predictor of malignant invasion in pulmonary malignancies when compared to gastrointestinal cancers. Endoscopic ultrasound-guided fine-needle aspiration of lymph nodes in 22 patients revealed malignant lymph node invasion in 16 and benign cells in 6 patients. CONCLUSION Endoscopic ultrasound-guided fine-needle aspiration is an important adjunct for accurate lymph node assessment for malignancy.

Complications of endoscopic sphincterotomy

Mostly retrospective series with limited use of sphincter of Oddi manometry have indicated that early complications are more common when endoscopic sphincterotomy is performed for sphincter of Oddi dysfunction than for common duct stones. The current study was undertaken to prospectively evaluate the frequency and type of complications of endoscopic sphincterotomy performed for sphincter of Oddi dysfunction compared with endoscopic sphincterotomy performed for other conditions. Four hundred twenty-three patients underwent sphincterotomy for sphincter of Oddi dysfunction (166), common duct stone(s) (163), tumor (60), and miscellaneous reasons (34). Patients were observed in the hospital for at least 24 hours after the procedure, and 30-day follow-up data were obtained. The overall complication rate was 6.9%, but complications were more frequent when sphincterotomy was performed for sphincter of Oddi dysfunction than for all other indications (10.8% vs. 4.3%; P = 0.009). Precut sphincterotomy was more frequently required in the sphincter of Oddi dysfunction group (21.1% vs. 11.7%, P = 0.009) but was no more likely to result in a complication (6.2%) than standard sphincterotomy. The risk of a complication was considerable for a small-diameter common bile duct (less than or equal to 5 mm), particularly when sphincterotomy was performed for sphincter of Oddi dysfunction (37.5%). The overall 30-day mortality rate was 1.7%, but the procedure-related mortality rate was believed to be 0.2%. It is concluded that endoscopic sphincterotomy for sphincter of Oddi dysfunction is more hazardous than for other conditions, particularly when a small common bile duct is present.

Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study

BACKGROUND The role of pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts remains unclear. OBJECTIVE Our purpose was to evaluate the utility of a detailed DNA analysis of pancreatic cyst fluid to diagnose mucinous and malignant cysts. DESIGN Prospective, multicenter study. PATIENTS Patients with pancreatic cysts presenting for EUS evaluation. INTERVENTION EUS-guided pancreatic cyst aspirates cytology evaluation, carcinoembryonic antigen (CEA) level determination, and a detailed DNA analysis; incorporating DNA quantification, k-ras mutation and multiple allelic loss analysis, mutational amplitude, and sequence determination. MAIN OUTCOME MEASUREMENTS Cyst fluid analysis compared with surgical pathologic or malignant cytologic examination. RESULTS The study cohort consisted of 113 patients with 40 malignant, 48 premalignant, and 25 benign cysts. Cyst fluid k-ras mutation was helpful in the diagnosis of mucinous cysts (odds ratio 20.9, specificity 96%), whereas receiver-operator characteristic curve analysis indicated optimal cutoff points for allelic loss amplitude (area under the curve [AUC] 0.79; optimal value > 65%) and CEA (AUC 0.74; optimal value >148 ng/mL). Components of DNA analysis detecting malignant cysts included allelic loss amplitude over 82% (AUC 0.9) and high DNA amount (optical density ratio >10, AUC 0.79). The criteria of a high amplitude k-ras mutation followed by allelic loss showed maximum specificity (96%) for malignancy. All malignant cysts with negative cytologic evaluation (10/40) could be diagnosed as malignant by using DNA analysis. LIMITATIONS Limited follow-up, selection bias. CONCLUSIONS Elevated amounts of pancreatic cyst fluid DNA, high-amplitude mutations, and specific mutation acquisition sequences are indicators of malignancy. The presence of a k-ras mutation is also indicative of a mucinous cyst. DNA analysis should be considered when cyst cytologic examination is negative for malignancy.

Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia

BACKGROUND & AIMS Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barretts esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Endoscopic Ultrasonography, Fine-Needle Aspiration Biopsy Guided by Endoscopic Ultrasonography, and Computed Tomography in the Preoperative Staging of Non-Small-Cell Lung Cancer: A Comparison Study

Accurate staging of non-small-cell lung cancer plays a crucial role in determining the treatment options available to patients with this disease. The preoperative documentation of metastasis to the mediastinal lymph nodes has therapeutic implications that have traditionally focused on palliation but more recently have included neoadjuvant strategies [1, 2]. Metastasis to the mediastinal lymph nodes occurs in nearly half of all patients with non-small-cell lung cancer. The development of mediastinal metastasis is probably the most frequent deterrent to cure, even when the presentation is localized. If metastasis involves contralateral or large, bulky (>1.5 to 2.0 cm) subcarinal lymph nodes, surgery alone may not be curative [3-9]. As a result of recent revisions to the staging systems for lung cancer, ipsilateral mediastinal and subcarinal lymph node involvement is now classified as potentially resectable, N2 disease; contralateral mediastinal lymph node involvement (N3 disease) precludes resection [10-12]. Computed tomography of the chest is the current method by which mediastinal lymphadenopathy is detected in non-small-cell lung cancer. However, its sensitivity for detection of metastasis to the lymph nodes varies; accuracy in previous studies has ranged from 52% to 88% [13-23]. This inconsistency has been attributed to the variable correlation of lymph node size with the presence of malignancy. When enlarged contralateral or ipsilateral mediastinal lymph nodes are seen on computed tomography of the chest, standard practice is to determine more accurate staging by performing aspiration biopsy of the lymph node with computed tomographic guidance; bronchoscopy; or, less commonly, a transthoracic approach. If these procedures are unsuccessful, open biopsy is performed by using mediastinoscopy or limited thoracotomy [24-26]. If contralateral lymph nodes are positive for malignancy, surgical resection of the primary tumor is contraindicated. The development of endoscopic ultrasonography has now made it possible to visualize, with high resolution, not only the gastrointestinal tract but also surrounding structures. Endoscopic ultrasonography has been shown to be superior to computed tomography in evaluating lymph nodes for metastases in esophageal, gastric, and pancreatic cancer [27-29]. Promising results for detecting posterior mediastinal lymph nodes in patients with lung cancer suggest a possible role for endoscopic ultrasonography in staging lymph nodes in patients with non-small-cell lung cancer [30-36]. Fine-needle aspiration biopsy guided by endoscopic ultrasonography was recently reported to further improve the accuracy of endoscopic ultrasonography in predicting malignancy of gastrointestinal masses, with rates as high as 87% to 91% [37-42]. We previously reported the results of endoscopic ultrasonography in 17 patients with lung cancer. This method was very accurate for detecting mediastinal lymphadenopathy; the overall accuracy was 71% compared with 41% for computed tomography (P = 0.032) [43]. During the initial study, however, fine-needle aspiration biopsy guided by endoscopic ultrasonography was not available. The goal of the present study was to prospectively evaluate the accuracy of endoscopic ultrasonography alone, endoscopic ultrasonography-guided fine-needle aspiration biopsy, and computed tomography of the chest in detecting mediastinal lymph node metastasis in patients with non-small-cell lung cancer. Methods Patient Selection The study sample consisted of all patients presenting to the Indiana University Thoracic Oncology Program between July 1993 and June 1995 with a diagnosis of non-small-cell lung cancer. The study was approved by the institutional review board, and all enrolled patients gave informed consent. Patients were excluded if they had documented unresectable disease (that is, distant metastasis or locally advanced staged disease [stage III b]) as shown on computed tomography of the chest or if they had a serious medical illness and a life expectancy of less than 1 year. All patients underwent initial preoperative intravenous contrast-enhanced computed tomography of the chest; the axial technique was used in 60% of patients, and the spiral technique was used in 40%. Computed tomography was done at the referring hospital or Indiana University Medical Center; the scans were read at Indiana University Medical Center by a senior attending radiologist who has recognized expertise in this area and used currently accepted radiographic techniques to stage the tumor. The radiologists determination of the benign or malignant nature of each lymph node was recorded on a preoperative computed tomography lymph node map; the American Thoracic Society mediastinal staging map (Figure 1) was used to describe the location of each node [12]. Any patient who had a questionably enlarged mediastinal lymph node (>1 cm in diameter) and was considered a surgical candidate was then scheduled for endoscopic ultrasonography. Figure 1. American Thoracic Society scheme for mapping mediastinal lymphadenopathy by anatomic location, as seen from behind with endoscopic ultrasonography. Endoscopic Ultrasonography Endoscopic ultrasonography was performed in an outpatient setting on all patients by one of three experienced endosonographers; the radial scanning echoendoscope (GFUM-20, Olympus America, Melville, New York) or the linear-array scanning echoendoscope (FG32UA, Pentax, Orangeburg, New York) was used for all procedures. When done by an experienced operator, endoscopic ultrasonography is similar to standard upper endoscopy both in technique and duration of the procedure. When fine-needle aspiration biopsy is performed, the procedure is slightly prolonged. Patients were sedated with meperidine and midazolam, the doses of which were titrated to achieve adequate conscious sedation. The instrument was advanced into the stomach, and the celiac axis was imaged. The probe was then withdrawn to the gastroesophageal junction and slowly withdrawn at 1-cm intervals. Images were obtained with 7.5- and 12-MHz frequencies at each interval. All imaged mediastinal lymph nodes were mapped by location according to the American Thoracic Society classification scheme [12]. From these data, an objective assessment was made as to whether the mediastinal lymphadenopathy detected by endoscopic ultrasonography was benign or possibly malignant according to the following previously reported criteria for malignancy: round shape; sharp, distinct borders; hypoechoic texture; and a short-axis diameter greater than 5 mm [36-39]. Malignancy was suspected if all of these criteria were present. All patients who were studied before the availability of endoscopic ultrasonography-guided fine-needle aspiration biopsy underwent surgical resection, and endoscopic ultrasonographic findings were correlated to surgical pathologic findings. Patients who were studied after the advent of fine-needle aspiration biopsy and were found to have no suspicious lymph nodes by endoscopic ultrasonography were directly referred for surgery because there was no indication for aspiration biopsy. Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Endoscopic ultrasonography-guided aspiration biopsy became available after the first 17 patients were enrolled in our pilot study. All posterior mediastinal lymph nodes that were suspicious for malignant involvement according to the endoscopic ultrasonographic criteria were noted; selected nodes underwent biopsy during the same procedure. Many of the patients had more than one suspicious lymph node. We performed biopsy only on the most suspicious lymph node, which would have the greatest effect on clinical staging (that is, determination of whether the metastasis was contralateral or subcarinal). This technique for ultrasonography-guided aspiration biopsy was initially developed for use with the linear-array instrument (Figure 2) and is described elsewhere [40-42]. We recently reported a similar technique that uses a radial scanning echoendoscope (Figure 3) [37]. Ultrasonography-guided aspiration biopsy involves the insertion of an aspiration catheter needle device through the accessory channel port of the echoendoscope; the needle is then deployed into the lymph node to be sampled under endoscopic ultrasonographic guidance. Aspiration biopsy is done by introducing a specially designed fine-needle aspiration catheter system that consists of a 4-cm long, 23-gauge needle attached to a 180-cm long, 5-French aspiration catheter (Wilson-Cook, Winston-Salem, North Carolina); in and out movements of the catheter are used while the operator firmly grasps the catheter at the point at which it enters the accessory port. Figure 2. A mediastinal lymph node as imaged with the linear-array endoscopic ultrasonography system. arrow Figure 3. Endoscopic ultrasonographic image obtained from the radial scanning instrument showing a large hypoechoic, oval subcarinal lymph node (LN) suspicious for metastatic involvement. Preliminary cytologic findings were obtained during fine-needle aspiration biopsy by a cytopathologist who was present during the procedure. Before the sample was reviewed, Diff-Quik stain (Harleco, Gibbstown, New Jersey) was applied to the slide that contained the deposited specimen. Additional passes were made until a positive cytologic result or a negative result on an adequate tissue sample was obtained [37]. Patients who were considered eligible for surgical resection after staging by computed tomography and endoscopic ultrasonography (that is, patients with a negative result on aspiration biopsy of contralateral or bulky subcarinal lymph nodes or those with nodes that seemed to be benign according to endoscopic ultrasonographic criteria) underwent thoracotomy for pulmonary resection with ipsilateral mediastinal and subcarinal lymph node dissection. During mediastinal dissection, each lymph node was placed in th