Multicenter study on the diagnostic performance of multiframe volumetric laser endomicroscopy targets for Barrett's esophagus neoplasia with histopathology correlation.

Volumetric laser endomicroscopy (VLE) has been shown to improve detection of early neoplasia in Barrett's esophagus (BE). However, diagnostic performance using histopathology-correlated VLE regions of interest (ROIs) has not been adequately studied. We evaluated the diagnostic accuracy of VLE assessors for identification of early BE neoplasia in histopathology-correlated VLE ROIs. In total, 191 ROIs (120 nondysplastic and 71 neoplastic) from 50 BE patients were evaluated in a random order using a web-based module. All ROIs contained histopathology correlations enabled by VLE laser marking. Assessors were blinded to endoscopic BE images and histology. ROIs were first scored as nondysplastic or neoplastic. Level of confidence was assigned to the predicted diagnosis. Outcome measures were: (i) diagnostic performance of VLE assessors for identification of BE neoplasia in all VLE ROIs, defined as accuracy, sensitivity, and specificity; (ii) diagnostic performance of VLE assessors for only high level of confidence predictions; and (iii) interobserver agreement. Accuracy, sensitivity, and specificity for BE neoplasia identification were 79% (confidence interval [CI], 75-83), 75% (CI, 71-79), and 81% (CI, 76-86), respectively. When neoplasia was identified with a high level of confidence, accuracy, sensitivity, and specificity were 88%, 83%, and 90%, respectively. The overall strength of interobserver agreement was fair (k = 0.29). VLE assessors can identify BE neoplasia with reasonable diagnostic accuracy in histopathology-correlated VLE ROIs, and accuracy is enhanced when BE neoplasia is identified with high level of confidence. Future work should focus on renewed VLE image reviewing criteria and real-time automatic assessment of VLE scans.

Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.

Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.

Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial.

BACKGROUND AND STUDY AIMS: The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia [CR-IM]) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up. PATIENTS AND METHODS: Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA. RESULTS: Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation [SD] 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR-IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval [CI] 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error [SE] 0.12). CONCLUSIONS: In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA.

Depth of resection using two different endoscopic mucosal resection techniques.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) has been carried out for high-grade dysplasia (HGD) and intramucosal carcinoma (IMCA) in Barrett's esophagus using two different cap-assisted techniques, the "inject, suck, and cut" and the "band and snare." Previous work has demonstrated comparable specimen diameters. However, the two techniques have not been previously compared with respect to depth of resection. PATIENTS AND METHODS: From a database of patients with Barrett's esophagus, we identified 40 consecutive specimens removed using EMR from patients with HGD or IMCA, 20 each from the "inject, suck, and cut" and the "band and snare" techniques. Specimens were evaluated and measured separately by two pathologists for greatest diameter and depth, and for the presence of submucosa and muscularis propria at the deepest margin of resection. Follow-up data were collected regarding clinical outcome and stricture formation. RESULTS: The mean depth of the specimens from the two techniques was not significantly different (0.51 cm vs. 0.50 cm, P = 0.76). All specimens contained substantial submucosa, allowing accurate staging of the neoplastic lesions resected. Muscularis propria was identified at the base of 65% of the "band and snare" and 50% of the "inject, suck, and cut" specimens (P = 0.52). CONCLUSIONS: The "inject, suck, and cut" and "band and snare" techniques both yield equivalent adequate depth of histological specimens from Barrett's esophagus with HGD or IMCA, and both provide accurate pathological staging.

Long-term follow-up of complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intramucosal carcinoma.

BACKGROUND AND STUDY AIMS: In patients with Barrett's esophagus (BE), targeted endoscopic mucosal resection (EMR) of visible lesions of high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) is effective, but carries the risk of leaving in place synchronous lesions and Barrett's epithelium with the potential for recurrent disease. We evaluated the safety and long-term efficacy of complete Barrett's eradication EMR (CBE-EMR) for the treatment of patients with HGD or IMC, independently of the presence of macroscopically visible lesions or surgical risk. PATIENTS AND METHODS: 26 consecutive patients with BE and HGD or IMC underwent CBE-EMRs, which were performed with the endoscopic cap suction method and/or a 2.3-mm monofilament mucosectomy snare. Endoscopic follow up after completion of resection was carried out to assess the rate of residual or recurrent BE with or without HGD or IMC. RESULTS: 24 patients completed the study. They underwent a total of 44 EMR sessions with a median of 3 pieces (range 1-8) removed per session. Two patients with immediate bleeding were successfully managed endoscopically. Three patients developed an early esophageal stricture that was completely resolved with a single endoscopic dilation. After a median follow-up of 28 months (range 15-51 months), persistent endoscopic and histologic eradication of BE was demonstrated in 21 patients (87.5 %). In two patients, Barrett's epithelium was detected beneath the neosquamous epithelium 3 months after completion of the resection. In the remaining patient, IMC was found in a nodule seen and removed by EMR at 12-month surveillance endoscopy. CONCLUSIONS: CBE-EMR is a safe and highly effective long-term treatment that should be offered to all patients with Barrett's esophagus with HGD and IMC.

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer.

PURPOSE: The trial was undertaken to determine the response rate to and toxicities from the combination of interferon alfa-2a (IFN) and fluorouracil (FU) in patients with advanced esophageal cancer. MATERIALS AND METHODS: In this prospective phase II trial conducted at a large tertiary referral cancer center and university hospital, 40 patients with advanced locoregional, metastatic epidermoid, or adenocarcinoma of the esophagus were given FU 750 mg/m2 by 24-hour continuous intravenous infusion days 1 to 5, followed by weekly outpatient bolus FU 750 mg/m2 and IFN 9 x 10(6) U three times per week from day 1. Dose was attenuated for fatigue, neurotoxicity, gastrointestinal toxicity, and myelosuppression. RESULTS: Complete and partial responses were seen in 10 of 37 assessable patients with esophageal cancer (27%; 95% confidence interval, 0.13 to 0.41). Although substantial, toxicity was tolerable and primarily involved fatigue and mild myelosuppression. The median duration of response was 6.4 months (range, 2.8 to 14+ months). CONCLUSION: The combination of IFN and FU is an active regimen in the treatment of advanced esophageal cancer with a response rate similar to that reported for cisplatin-containing combinations in similar patient populations. Further studies based on this combination are indicated.

Preoperative endoscopic ultrasound can predict the risk of recurrence after operation for gastric carcinoma.

PURPOSE: Endoscopic ultrasonography (EUS) has been shown to determine accurately the depth of invasion of the stomach wall in gastric carcinoma. We undertook this study to determine if T (tumor) stage as determined by EUS correlated with recurrence after resection and could be used to identify patients preoperatively at high risk for recurrence. MATERIALS AND METHODS: We reviewed the surgical pathology and obtained follow-up data from the first 50 patients who underwent preoperative EUS for staging of gastric carcinoma. Rotating sector-scan ultrasound endoscopes were used with switchable frequencies of 7.5 MHz and 12 MHz. RESULTS: Of 50 patients, 43 underwent resection with curative intent and were available for follow-up. The concordance of EUS T stage with pathologic T stage in these patients was 86%. At a median follow-up duration of 25 months, only two of 13 patients with preoperative EUS stage T1 or T2 disease were found to have recurrence, while 23 of 30 patients with EUS stage T3 or T4 disease had recurrence (P = .0002) and 22 died. CONCLUSION: We conclude that patients with a preoperative EUS stage T1 or T2 are at low risk for postoperative recurrence, while patients with EUS stage T3 or T4 are at high risk for early postoperative recurrence. The latter patients are reasonable candidates for controlled trials of alternative preoperative management programs, such as chemotherapy, in an effort to improve their poor prognosis.

FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer.

PURPOSE: The chemotherapy regimens of high-dose methotrexate, high-dose fluorouracil (FU), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and leucovorin (FAMTX) and etoposide, Adriamycin, and cisplatin (EAP) have both been reported in nonrandom assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer, as well as major toxicities of myelosuppression. Here we report a prospective, stratified, random-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer. PATIENTS AND METHODS: Sixty patients were entered onto the trial, 30 receiving EAP and 30 FAMTX. All patients had measurable or assessable tumor masses. Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis. RESULTS: Response rates were similar between the two arms (FAMTX, 33% [95% confidence interval (CI), 16% to 50%]; EAP, 20% [95% Cl, 6% to 34%]). Three FAMTX and no EAP patients had complete remissions. The median survival for the two arms were similar (EAP, 6.1 months; FAMTX, 7.3 months). At 1 year, 7% of EAP and 17% of FAMTX patients were alive. EAP caused significantly more myelosuppression (leukopenia, P = .002; anemia, P = .03; thrombocytopenia, P = .0001) than did FAMTX. EAP also resulted in significantly longer hospitalizations per study month (8 v 5 days). Four EAP patients died of lethal toxicity, whereas no FAMTX patients died of treatment-related causes (P = .04). CONCLUSIONS: FAMTX is at least as active as EAP and is significantly less toxic. Although both regimens remain investigational, the toxicities of FAMTX are more manageable. Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway.

Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil.

PURPOSE AND METHODS: We identified patients with gastric cancer at high risk for recurrence before therapy using endoscopic ultrasonography (EUS). Neoadjuvant therapy using the fluorouracil, doxorubicin, and metrotrexate (FAMTX) regimen was given for three courses before planned laparotomy with the intention to perform curative resection. Postoperatively, intraperitoneal (IP) cisplatin and fluorouracil (FU) and intravenous (i.v.) FU were administered to patients undergoing resection. RESULTS: Fifty-six assessable patients were treated. Preoperative FAMTX therapy was tolerable, with the major toxicity being neutropenic fever. One treatment-related death was seen. Eighty-nine percent of patients underwent surgical exploration and 61% had potentially curative resections. There were two postoperative deaths. Comparison of pathologic tumor (pT) stage with EUS-predicted tumor stage showed apparent downstaging in 51% of patients. Postoperative IP chemotherapy was delivered to 75% of eligible patients. Toxicity was acceptable. There was no increase in operative morbidity or mortality compared with concurrent nonstudy patients undergoing a similar operative procedure and not receiving preoperative therapy. With a median follow-up time of 29 months, the median survival duration was 15.3 months. For patients who underwent potentially curative resections, the median survival duration was 31 months. Peritoneal failure was seen in 16% of patients. CONCLUSION: Chemotherapy with the FAMTX regimen is tolerable in patients with locally advanced gastric cancer, without an increase in operative morbidity or mortality. IP therapy can be successfully delivered to most resected patients. The intraabdominal failure pattern appears to be decreased compared with expected. This approach is an appropriate investigational arm to pursue in future studies.

Increased expression of the cyclin D1 gene in Barrett's esophagus.

Previous studies have found a 3-10-fold amplification and overexpression of the cyclin D1 gene in about 32% of human esophageal squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of increased expression of the cyclin D1 protein in Barrett's esophagus. Using 69 formalin-fixed and paraffin-embedded human esophageal specimens, which had been removed endoscopically or obtained at surgery during 1993 and 1994, all immunohistochemical analyses were performed using an avidin-biotin complex immunoperoxidase technique. Increased nuclear expression of the cyclin D1 protein was noted in 32 of 69 samples (46%; 44% of the samples from males and 50% of the samples from females). Positive nuclear staining for the cyclin D1 protein in Barrett's disease with intestinal metaplasia was found in 38% of the male cases and 25% of the female cases, whereas in gastric metaplasia it was positive in 33% of men and 48% of women. Nuclear accumulation of the cyclin D1 protein was also found in both dysplastic and nondysplastic lesions, and it was not associated with sex, age, or cigarette or alcohol consumption. Samples from patients taking proton pump inhibitors tended to be less frequently positive (32%) for cyclin D1 nuclear staining when compared to patients taking H2 antagonists (45%) or antacids (55%). These studies suggest that increased expression of cyclin D1 is an early event in the tumorigenic process of esophageal adenocarcinomas and that the increased expression of this gene might predispose the epithelium to malignant transformation.

Screening diagnosis and staging of esophageal cancer.

In geographic areas where there is a high risk of esophageal cancer, analysis of cells obtained from the esophagus has been used effectively to detect early lesions. This has been demonstrated on a large scale in studies from China. Using abrasive balloon cytology techniques, 75% of the cancers detected were early lesions, where the 5-year survival after resection was in the range of 90%. Endoscopic followup studies indicate that dysplastic changes in the esophageal mucosa are a common precursor to malignancy. In many cases, the time course from dysplasia to carcinoma in situ to early invasive cancer may take place over many years, allowing a reasonable amount of time for screening. In low-incidence areas, such as the United States, most esophageal cancers are related to the excessive use of tobacco and alcohol. These factors are too common and the incidence of the disease too low, however, to justify screening on this basis. There are smaller groups at higher risk where selective screening by endoscopy with cytology and biopsy is recommended, usually every 1 to 3 years. These include patients with longstanding achalasia, lye strictures, and Plummer- Vinson syndrome. Patients with cancers of the head and neck region and patients with celiac disease may also be considered to be at increased risk. Tylosis is a rare inherited disease with a very high risk of esophageal cancer. There is an increased incidence of adenocarcinoma of the esophagus with Barrett's epithelium, and once identified such patients should be kept under endoscopic surveillance. The finding of severe dysplasia in any of these groups would indicate a shorter screening interval. Most patients with symptoms referable to the esophagus are first tested by barium esophagram. If negative, with persistent symptoms or if a suspicious lesion is identified, endoscopy with cytology and biopsy is recommended. Staging of the cancer is based on the size of the cancer both longitudinally and circumferentially and the presence of extraesophageal spread. At the present time, CT is the best noninvasive method for judging the extent of the cancer. Performance and nutritional status are also determinants of prognosis and should be considered in planning treatment.

Familial pancreatic cancer: a review.

The cause of pancreatic cancer remains elusive. The most consistently identified epidemiological risk factor is cigarette smoking. Genetic factors are known to play a significant role in perhaps 5% of the total pancreatic cancer burden. Recent discoveries in molecular biology, particularly germline mutations in inherited conditions which feature pancreatic cancer as an integral part of the tumor spectrum such as in adenomatosis polyposis and hereditary nonpolyposis colorectal cancer, provide powerful incentive to search for other "cancer genes" in this heterogeneous disease. Early detection of this dreadful disease is crucial because its mortality rate approximates its incidence; the ability to identify high-risk patients on the basis of genetic analysis would significantly enhance the potential for early diagnosis. This review addresses the genetic epidemiology of pancreatic cancer and updates our views on screening, surgery, chemotherapy, and genetic counseling, all of which must be used to gain value from genetic predictability of risk status.

Carcinoma complicating Crohn's disease. Report of seven cases and review of the literature.

Seven cases of adenocarcinoma complicating Crohn's disease are reviewed. In three of the patients, small bowel cancers developed in association with reginal enteritis. In four patients, carcinoma of the colon was superimposed on Crohn's colitis. In two of these, the adenocarcinoma infiltrated chronic colocutaneous fistulas. Review of the literature shows an increasing number of reports of carcinoma complicating Crohn's disease, with a total of 36 cases of small bowel cancer and 30 cases of colon cancer previously reported. The significane of these and our own cases is discussed. The possibility of carcinoma must be kept in mind by clinicians following patients with Crohn's disease. Adenocarcinoma complicating Crohn's disease occurs at a younger age, on the average, and in areas similar to the distribution of Crohn's disease rather than the usual distribution of the cancer. Preoperative diagnosis is difficult, but changes in the nature of chronic fistulas should be investigated.

Ultrasound directed extrahepatic bile duct intraluminal brachytherapy.

Intraluminal brachytherapy with a transcatheter Iridium-192 (Ir-192) wire, as a method to deliver a boost to patients with tumors of the extrahepatic bile ducts, has been well described. A major limitation of current imaging techniques is the inability to accurately define the proximal, distal, and most importantly the lateral extent of the tumor. We have found endoluminal ultrasound, which to this date has been used primarily to measure arterial wall layers, can successfully determine tumor volume in the bile ducts. The small diameter of these ultrasound probes allows easy insertion into a biliary duct drainage tube. Given the uncertainties in the determination of tumor size in the bile ducts, ultrasound is an ideal method by which to obtain the measurements. We present a case of recurrent islet cell carcinoma treated with external beam radiation therapy and an Ir-192 intraluminal brachytherapy boost in which the ultrasound probe was used to determine the tumor volume and response to therapy.

Effects of psyllium fiber and short-chain organic acids derived from fiber breakdown on colonic epithelial cells from high-risk patients.

The effect of a purified fiber, psyllium and the short-chain organic acids derived from fiber breakdown, were assayed on isolated colonic epithelial cells primary-cultured from patients at high-risk of colon cancer, due to adenoma growth or family history of colon cancer. Psyllium fiber provided colonocytes some protection from deoxycholic acid-induced lysis. Propionic acid, a product of fiber breakdown, was a potent colonocyte mitogen, suggesting that fiber could indirectly protect the colon by providing colonocyte nutrients.

Endoscopic ultrasonography of the upper gastrointestinal tract.

Endoscopic ultrasonography combines the advantages of conventional endoscopy with the capabilities of ultrasonography. This permits the examiner to see through the wall of the gastrointestinal tract. The close proximity permits the use of relatively high frequencies, with the resulting increase in tissue contrast and resolution. There are limitations to its use, however, with the main one being a field of view limited to a 7-cm radius. Discussed in this article is its use for the gastrointestinal wall, the esophagus, the stomach, the duodenum, and the pancreas.

Detection of anastomotic recurrence by endoscopic ultrasonography.

There seems little doubt that endoscopic ultrasonography is highly sensitive and significantly better than computed tomography for the diagnosis of recurrent cancer at the surgical anastomosis after resection of esophageal and gastric cancer. The impact of using EUS for this purpose is discussed.

Role of photodynamic therapy in the management of advanced esophageal cancer.

Esophageal cancer usually presents at an advanced stage with dysphagia, and palliative therapy often is appropriate. Expandable metal stents are used for palliation because of their ease of insertion, but long-term complications remain common. Photodynamic therapy has been shown to be an effective ablative treatment for obstructing esophageal cancer, overall easier to use, and longer lasting than Nd:YAG laser ablation. Photodynamic therapy may be particularly useful in areas where stents may be problematic, such as in the upper esophagus, at the esophagogastric junction (where adenocarcinomas are increasing in frequency), and following radiation and chemotherapy.

The role of endosonography in the diagnosis and management of pancreatic cancer.

Among the various diagnostic tests that may be used to detect and stage pancreatic cancer, endoscopic ultrasound (EUS) is among the most promising. It is a highly sensitive test for detecting pancreatic tumors and for detecting the invasion of these tumors into the portal venous system or loco-regional lymph nodes. With the development of EUS-guided fine-needle puncture, tissue diagnosis of imaged lesions is now possible. This latest advance has improved the specificity and overall accuracy of EUS and also allows for the development of therapeutic applications, such as celiac plexus neurolysis. In this article we review the materials, methods, and clinical applications of EUS for the evaluation of pancreatic cancer.

Aspiration and brush cytology of the liver.

In this study, 1,650 liver aspirates and laparoscopic brushings, representing a wide range of neoplastic and nonneoplastic conditions were examined cytologically. Of the 470 cytologic malignancies, only one was a false-positive. The most frequently diagnosed malignant neoplasms were carcinomas of the colon, breast, pancreas, lung, and liver. The overall accuracy rate of cytologic examination was 96%, with a sensitivity of 94%, and a specificity of 100%. Predictive values for both positive and negative results, were high: 100% and 95%, respectively. Reviewing the literature on aspiration cytology of the liver, we found that our results confirmed the findings of others: that cytologic examination of liver aspirates and brushings is a safe, useful, and accurate technique and may obviate tissue biopsy in cases of tumors metastatic to the liver.