Analysis of protein expression patterns in Barrett's esophagus using MALDI mass spectrometry, in search of malignancy biomarkers.

SUMMARY: In order to detect early changes of malignant degeneration in Barrett's esophagus (BE), and to reduce the cost of surveillance, molecular biomarkers of early malignancy have been sought, with limited success, using genomic and immunohistochemical tools. We postulate that direct analysis of epithelial proteins using mass spectrometry will provide protein profiles capable of identifying patients at high risk of developing malignancy. Our aim is to find transitional protein signals that show a cancer profile within histologically benign BE, which can be used as indicators of early malignant change. Fourteen fresh-frozen, resected esophageal cancer specimens were analyzed using laser capture microdissection and matrix-assisted laser desorption/ionization mass spectrometry. Samples of squamous epithelium, and both benign and malignant Barrett's epithelium, were compared for differences in protein expression. Reliable differentiation of squamous and Barrett's epithelium was demonstrated. A comparison of benign and malignant Barrett's epithelium identified a number of cancer-specific protein peaks that were deletion or expression variations from benign epithelium. In four instances the proteins (7350, 8446, 10850, and 14693) appeared to be early malignant changes in histologically benign BE. Mass spectrometry performed upon fresh-frozen Barrett's epithelium, obtained by laser-capture microdissection, displays reproducible, tissue-specific, protein profiles. Distinct differences are demonstrated between benign and malignant epithelium, some of which appear to be candidate biomarkers of early malignant change. This technique reliably displays cellular protein expression in esophageal epithelium and deserves further study as a tool to identify early malignant degeneration in BE.

Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer.

OBJECTIVE: Endoscopic surveillance of Barrett's esophagus is commonly practiced to detect malignancy in an early and curable stage. However, the cost-effectiveness of this practice has been questioned. To clarify this issue, we undertook a cost analysis of endoscopic surveillance to detect adenocarcinoma in Barrett's esophagus compared with mammography used to detect occult carcinoma of the breast, a widely accepted cancer surveillance technique. METHODS: The rate of esophageal adenocarcinoma detected by endoscopic surveillance was calculated for Duluth Clinic patients with Barrett's esophagus seen from 1980 to 1995 and compared with published rates. The rate of occult breast cancer detection was calculated for all women undergoing surveillance mammography at the Duluth Clinic for the year 1994 and compared with published rates. Costs for screening studies and therapy for cancer treatment for both cancers were calculated based on clinical results and assumptions regarding outcomes derived from published reports, and the costs were compared. RESULTS: Endoscopic surveillance of 149 patients with benign Barrett's esophagus was performed for a total of 510 patient-yr, during which time seven patients developed adenocarcinoma, an incidence of one case per 73 patient-yr of follow-up. Occult breast cancer was detected in 50 of 12,537 mammograms, a detection rate of 0.4%. The incidences in both cases were comparable to published figures. The costs of detecting a case of adenocarcinoma in Barrett's esophagus and occult breast cancer were $37,928 and $54,513, respectively, and those for treatment resulting in cure were $83,340 and $83,292. Cost per life-yr saved was $4,151 for adenocarcinoma in Barrett's esophagus and $57,926 for breast cancer. CONCLUSION: Endoscopic surveillance of patients with Barrett's esophagus compares favorably with the common practice of surveillance mammography to detect early breast cancer, and should therefore be considered to be as cost-effective as surveillance mammography.

Repair of aortoesophageal fistula after aortic grafting.

This report describes repair of an aortoesophageal fistula caused by a previously placed thoracic aortic graft. The diagnosis was made by esophagoscopy. The repair consisted of femoral-to-femoral cardiopulmonary bypass, excision of the old graft, placement of a new graft, esophagectomy, cervical esophagostomy, gastrostomy, and later reconstruction by cervical esophagogastrostomy.

Objective assessment of gastroesophageal reflux after short esophagomyotomy for achalasia with the use of manometry and pH monitoring.

The role of an antireflux procedure as an adjunct to esophagomyotomy for achalasia remains a subject of controversy. Little objective documentation exists of this operation's effect on sphincteric competence and the degree of postoperative gastroesophageal reflux. This report of esophageal manometry and 24-hour pH monitoring on 14 patients with esophageal achalasia whom we had previously treated by a short esophagomyotomy without an antireflux procedure provides such documentation. Esophagomyotomy reduced lower esophageal sphincter pressure by 12% to 71% (mean 41%) from a preoperative mean of 26.7 mm Hg to a postoperative mean of 14.6 mm Hg. The number of postoperative episodes of acid reflux per patient in 24 hours was fewer than 29 (normal < 49) in 13 patients, with a median of 12 episodes for the entire group. Esophageal acid exposure, measured as percentage of total time with pH less than 4.0 (normal < 4.5%), was below 4.5% in 10 patients, six of whom had values less than 1%. Among the four patients with values greater than 4.5%, only one had a temporal correlation of symptoms with an episode of acid reflux. Multivariate analysis showed that esophageal acid exposure time correlated only with the level of residual lower esophageal sphincter pressure during the relaxation phase of deglutition. A pressure less than 8 mm Hg was predictive of normal acid contact time (p < 0.001). Mean lower esophageal sphincter pressure, percent reduction in lower esophageal sphincter amplitude, postoperative vector volume, and length of the lower esophageal sphincter did not significantly correlate with amount of esophageal acid exposure. We conclude that a short esophagomyotomy without an antireflux procedure results in a competent lower esophageal sphincter in most patients. Increased esophageal acid exposure, when it occurs, is due to slow clearance of esophageal acid from relatively few reflux episodes and is more likely to occur when there is a high residual pressure during deglutition after myotomy. These findings suggest that the addition of an antireflux procedure to a short esophagomyotomy would not be expected to improve clinical results.

Idiopathic subglottic stenosis.

OBJECTIVE: To review our patients with subglottic stenosis and describe a rare subclass of patients in whom the cause of subglottic scarring and narrowing remains unknown. DESIGN: A retrospective chart review and clinical update were performed on all patients seen with the diagnosis of subglottic stenosis. SETTING: The patient pool represents a collection of primary care patients within a suburb of Boston, Mass, and tertiary referrals from community and out-of-state otolaryngologists. PATIENTS: The charts of 80 patients were reviewed, and 10 of the 80 patients fulfilled the criteria for idiopathic subglottic stenosis. INTERVENTION: Diagnostic and therapeutic intervention ranged from laboratory tests, topography, flexible bronchoscopy, rigid endoscopy and biopsy, laser-assisted dilation, and resection and repair of the lesion. MAIN OUTCOME MEASURES: Attention was directed toward the character of the lesion, treatment modality, and clinical outcome. RESULTS: From 1985 to 1992, 10 patients with idiopathic subglottic stenosis were treated at the Lahey Clinic, Burlington, Mass. Eight patients required therapy for exertional dyspnea. Endoscopic laser incision and dilation were performed in all eight patients, with good initial results. Four patients were treated successfully with endoscopy alone: three required only one dilation, and the fourth required a second dilation. The remaining four patients, who had longer and more complex stenoses, have had repeated restenosis at intervals ranging from 1.5 to 12 months. Two of these patients have undergone laryngotracheal resection and reconstruction and were without evidence of restenosis 10 and 20 months after surgery. CONCLUSIONS: There exists a subclass of patients with subglottic stenosis of unknown cause. Symptomatic idiopathic subglottic stenosis may be treated successfully with laser incision and dilation if the stenosis is simple and short. More complex, longer stenoses are prone to recurrence and are more definitively managed by resection and reconstruction of the narrowed area.

Achalasia and squamous cell carcinoma of the esophagus: analysis of 241 patients.

Achalasia of the esophagus is presumed by many to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. There is disagreement, however, as to the precise risk of malignant degeneration and there is no consensus as to either the need for close surveillance of achalasia patients or the surveillance technique that should be employed. A review of the available literature on the subject has disclosed a wide range of reported cancer risks in achalasia patients, from zero to 33 times that of the normal population. Cancers, when discovered, are often unresectable and the median survival when they are resectable is low. A personal experience with 241 achalasia patients treated during the past quarter of a century disclosed that 9 had carcinoma, for a prevalence of 3.7%. Carcinoma developed in 3 of these 9 while they were under our observation. This translates into one cancer per 1,138 patient-years of follow-up, an incidence of 88 per 100,000 population, and a risk 14.5 times that of the age-adjusted and sex-adjusted general population. Because of the low postresection survival rate if treatment is delayed until carcinoma of the esophagus becomes symptomatic, closer surveillance of achalasia patients is recommended than has been the case. Because it seems unlikely that close endoscopic surveillance will prove to be cost-effective, periodic (every 2 to 3 years) blind brush biopsy warrants further study as a means of surveillance.

Barrett's esophagus and esophageal cancer.

Adenocarcinoma arising in Barrett's esophagus is increasing in incidence and accounts for a substantial portion of intrathoracic esophageal malignancies today. Patients with Barrett's esophagus have a 50 to 100 times increase in their risk of developing cancer compared to the general population. Malignant degeneration of the columnar epithelium appears to pass through a phase of dysplasia prior to the development of invasive malignancy. Low-grade dysplasia often remains stable or regresses. High-grade dysplasia, however, is considered equivalent to carcinoma in situ and is a predictor of imminent or existing invasive cancer. Endoscopic surveillance can detect malignant change at an early stage when it is likely to be curable by surgery. Patients undergoing endoscopic surveillance of Barrett's esophagus compared to those not under surveillance have a significantly improved postoperative survival owing to earlier detection.

Paraesophageal hiatal hernia: is an antireflux procedure necessary?

Between January 1970 and October 1992, 119 patients underwent 126 repairs of a paraesophageal hiatal hernia at the Lahey Clinic. Seven patients with a recurrent hernia required reoperation. Of the procedures, 19 (15%) included an antireflux procedure because of severe reflux symptoms and objective evidence of reflux demonstrated by grade 2 esophagitis on endoscopy, manometric evidence of a hypotensive lower esophageal sphincter pressure (< or = 10 mm Hg), positive results on 24-hour pH monitoring, or all three methods. Follow-up ranged from 6 months to 18 years with a median of 61.5 months, and the results of 115 operations were analyzed. Symptomatic results were good to excellent after 96 (83.5%) of these 115 operations. Thirteen symptomatic paraesophageal hernias recurred in 12 patients (one recurrence per 58 patient-years of follow-up). Severe reflux symptoms accompanied by endoscopic evidence of esophagitis developed in 2 patients who had not undergone an antireflux procedure at the time of repair of the hernia. We conclude that an antireflux procedure is rarely required in patients undergoing repair of a paraesophageal hiatal hernia and should be employed only when objective evidence of reflux is seen preoperatively.

Endoscopic surveillance of Barrett's esophagus. Does it help?

Patients with Barrett's esophagus are recognized as having a high risk of development of adenocarcinoma. Although endoscopic surveillance of these patients is commonly practiced, its benefits have not been proved. This study was undertaken to examine the effect of endoscopic surveillance on the stage of resected carcinoma arising in Barrett's esophagus and the effect on postoperative survival. Between 1973 and 1991, 77 patients with adenocarcinoma were seen by us, and 19 of them were under endoscopic surveillance. The 19 patients underwent endoscopic biopsies at 1-month to 4-year intervals (median 6 months). All but one patient underwent esophagogastrectomy when severe dysplasia or invasive carcinoma was detected. The stages of the resected carcinomas in the group under surveillance compared with the group not under surveillance were significantly different, 58% of the patients under surveillance having stages 0 and I disease and 21% having stage III disease compared with 17% of the patients not under surveillance having stages 0 and I disease and 47% having stage III disease (p = 0.006). The 5-year actuarial survival of patients undergoing routine surveillance was 62% and of patients not under surveillance, 20% (p = 0.007). Endoscopic surveillance of patients with benign Barrett's esophagus permits detection of carcinoma at an early stage and improves long-term survival after resection for severe dysplasia and invasive carcinoma.

Traumatic dislocation of testes and bladder rupture.

Traumatic dislocation of the testes with bladder rupture occurred in 2 multiply injured patients with pelvic fracture. One had a history of retractile testes and the other of previous testicular dislocation. Surgical correction was performed after closed reduction failed. These injuries must be recognized and treated promptly to maximize the likelihood of testicular salvage. If early intervention is not possible, duplex ultrasonography and pulsed Doppler analysis are the optional valuative studies.

Current concepts concerning the nature and treatment of Barrett's esophagus and its complications.

Current concepts regarding the nature and the treatment of Barrett's esophagus and its complications are reviewed. The columnar-lined lower esophagus is being increasingly recognized as an acquired condition caused by gastroesophageal reflux. Many patients are asymptomatic. Barrett's esophagus occurs in about 10% to 15% of patients with reflux esophagitis. The diagnosis depends on endoscopy and biopsy. Complications are common and include ulceration, stricture, dysplasia, and adenocarcinoma. Esophagitis, ulceration, and stricture can usually be treated medically. Surgical approaches are discussed for patients whose condition is refractory to medical therapy. The premalignant nature of Barrett's epithelium is well recognized, and strategies for surveillance and resection are discussed. Survival after resection of adenocarcinoma in Barrett's esophagus is not appreciably different from that of other carcinomas. Surveillance with endoscopy offers the best chance for early detection and cure.

Subfascial implantation of implantable cardioverter defibrillator generator.

The automatic cardioverter defibrillator generator is a relatively large unit, which has most often been implanted in a subcutaneous pocket. In a consecutive series of 120 primary implantations, we employed a subrectus fascia pocket that has resulted in a cosmetically superior result with a 0.8% incidence of system infection. The technique of subfascial implantation is described.

Selective use of myotomy for treatment of epiphrenic diverticula. Manometric and clinical analysis.

The pathogenesis and treatment of epiphrenic diverticula remain controversial subjects. Most surgeons recommend esophagomyotomy in association with diverticulectomy in every patient. We believe that selective use of myotomy, based on manometry, should be used. From 1960 to 1990, 16 patients underwent surgical treatment for epiphrenic diverticulum at the Lahey Clinic Medical Center, Burlington, Mass. Six patients, three of whom underwent diverticulectomy alone and three who underwent an associated long myotomy, had the lower esophageal sphincter left intact; long-term results were good in all patients. The remaining 10 patients underwent myotomy of the lower esophageal sphincter. Reflux esophagitis developed in two of these patients who had a normal lower esophageal sphincter. Clinical results support the selective use of esophagomyotomy applied to areas of demonstrated dysmotility. A normal lower esophageal sphincter should be left intact to prevent reflux complications.

Airway injury after tracheotomy and endotracheal intubation.

Iatrogenic airway injury after tracheotomy and endotracheal intubation continues to be a serious clinical problem. Endotracheal tubes cause pressure injury to the glottis and may result in severe commissural scarring that is difficult to treat. Tracheotomy tubes may result in severe stomal stenosis in the trachea or subglottic region, which is more amenable to surgical treatment. Both methods of airway intubation may result in pressure necrosis from the tube cuff that can be prevented by careful monitoring of inflation pressures. The technique of laryngotracheal resection and reconstruction has been well developed and may be applied successfully to most patients with subglottic and tracheal stenosis. The surgical treatment of glottic stenosis remains a challenge.

Complications of percutaneous dart therapy in management of pneumothorax.

Treatment of patients who have pneumothorax is increasingly being undertaken with a small-diameter dart catheter. Although the catheter usually is effective, complications can arise with its use. We describe a patient in whom empyema developed during treatment of spontaneous pneumothorax with the use of such a catheter. Limitations and guidelines for its use are discussed.

Adenocarcinoma in Barrett's esophagus. A clinicopathologic study of 65 cases.

The natural history of Barrett's esophagus, particularly the prevalence and incidence of malignant changes in it, remains controversial. Furthermore the prognosis of surgically treated patients with carcinoma in Barrett's esophagus has not been elucidated fully. To examine these and other issues, the records of 65 patients with carcinoma in Barrett's esophagus presenting at the Lahey Clinic Medical Center from January 1973 to January 1989 were reviewed. During this period, 241 patients with documented Barrett's esophagus were seen, for a prevalence of carcinoma of 27%. Adenocarcinoma in Barrett's esophagus accounted for 30% of the surgically treated carcinomas of the thoracic esophagus during this period. All but four of these patients were men. Symptoms of chronic reflux were present in less than one half of the patients and dysphagia was often the presenting symptom. In eight patients the carcinoma was discovered on routine surveillance endoscopy, and in four patients progression of disease from benign columnar epithelium to dysplasia to carcinoma was documented. Tumors developed in six patients who had undergone previous antireflux surgery, and in four other patients a second carcinoma developed in residual Barrett's epithelium after a previous resection. Of the 65 patients, 61 (94%) were considered to have operable disease, all of whom underwent resection. Two patients (3.3%) died within 30 days of operation. The resected specimens were staged as follows: stage 0, 4; stage I, 10; stage II, 17; stage III, 25; stage IV, 4. Of the resected specimens, 73% showed areas of dysplasia adjacent to the tumor. The overall adjusted actuarial 5-year survival rate was 23.7%. The 3-year survival rate was 100% for patients with stage 0 carcinoma, 85.7% for patients with stage I carcinoma, 53.6% for patients with stage IIA carcinoma, 45% for patients with stage IIB carcinoma, 25.2% for patients with stage III carcinoma, and 0% for patients with stage IV carcinoma. The premalignant nature of Barrett's esophagus requires endoscopic surveillance to detect early carcinoma because symptoms often occur late or are absent. Antireflux surgery does not protect against the development of carcinoma. All of the Barrett's epithelium must be resected because a second carcinoma may develop in residual columnar epithelium. Severe dysplasia should be considered an indication for resection. Although operability and resectability rates are high, long-term survival is not. Early detection is mandatory if long-term survival is to be achieved.