Worldwide Esophageal Cancer Collaboration: pathologic staging data.

We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning.

Worldwide Esophageal Cancer Collaboration: clinical staging data.

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.

Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.

To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection.

Decreased core muscle size is associated with worse patient survival following esophagectomy for cancer.

Preoperative risk assessment, particularly for patient frailty, remains largely subjective. This study evaluated the relationship between core muscle size and patient outcomes following esophagectomy for malignancy. Using preoperative computed tomography scans in 230 subjects who had undergone transhiatal esophagectomy for cancer between 2001 and 2010, lean psoas area (LPA), measured at the fourth lumbar vertebra, was determined. Cox proportional hazards regression was employed to analyze overall survival (OS) and disease-free survival (DFS) adjusted for age, gender, and stage, and the Akaike information criterion was used to determine each covariate contribution to OS and DFS. Univariate analysis demonstrated that increasing LPA correlated with both OS (P = 0.017) and DFS (P = 0.038). In multivariate analysis controlling for patient and tumor characteristics, LPA correlated with OS and DFS in patients who had not received neoadjuvant treatment (n = 64), with higher LPA associated with improved OS and DFS. Moreover, LPA was of equivalent, or slightly higher importance than pathologic stage. These measures were not predictive among patients (n = 166) receiving neoadjuvant chemoradiation. Core muscle size appears to be an independent predictor of both OS and DFS, as significant as tumor stage, in patients following transhiatal esophagectomy. Changes in muscle mass related to preoperative treatment may confound this effect. Assessment of core muscle size may provide an additional objective measure for risk stratification prior to undergoing esophagectomy.

Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EA) is characterized by a poor prognosis making the identification of clinically targetable proteins essential for improving patient outcome. We report the involvement of multiple alterations of the MET pathway in EA development and progression. Microarray analysis of Barrett's metaplasia, dysplasia, and EA revealed overexpression of the MET oncogene in EAs but only those with MET gene amplification. STS-amplification mapping revealed that the boundary of the MET amplicon in these EAs is defined by fragile site FRA7G. We also identified an amplicon at 11p13 that resulted in amplification and overexpression of CD44, a gene involved in MET autophosphorylation upon HGF stimulation. Tissue microarrays with phospho-MET-specific antibodies demonstrated a uniformly high abundance of MET activation in primary EA and cells metastatic to lymph nodes but to a lesser extent in a subset of metaplastic and dysplastic Barrett's samples. Increased expression of multiple genes in the MET pathway associated with invasive growth, for example, many MMPs and osteopontin, also was found in EAs. Treatment of EA-derived cell lines with geldanamycin, an inhibitor for tyrosine kinases including MET receptor kinase, reduced cell migration and induced EA cell apoptosis. The data indicate that upregulation of the MET pathway may contribute to the poor outcome of EA patients and that therapeutic agents targeting this pathway may help improve patient survival.

Esophagectomy for achalasia: patient selection and clinical experience.

BACKGROUND: In 1989, we predicted an increasing number of esophagectomies for megaesophagus and for recurrent symptoms after prior esophagomyotomy or balloon dilatation for achalasia. Patient selection in this group is challenging, as the potential operative morbidity of an esophagectomy must be weighed against the expected clinical outcome after a redo esophagomyotomy or alternative procedures designed to salvage the native esophagus. METHODS: The hospital records of 93 patients undergoing esophagectomy for achalasia during the past 20 years were reviewed retrospectively and the results of operation assessed using our prospectively established Esophageal Resection Database and follow-up information obtained through personal contact with the patients. RESULTS: Patient age averaged 51 years. Indications for esophagectomy included tortuous megaesophagus (64%), failure of prior myotomy (63%), and associated reflux stricture (7%). Ninety-four percent of the patients underwent a transhiatal esophagectomy. Stomach was used as the esophageal substitute in 91% cases. Intraoperative blood loss averaged 672 mL. Postoperative length of stay averaged 12.5 days. Major complications included anastomotic leak (10%), recurrent laryngeal nerve injury (5%), delayed mediastinal bleeding requiring thoracotomy (2%), and chylothorax (2%). There were 2 hospital deaths (2%) from respiratory insufficiency and sepsis. Follow-up has averaged 38 months. In all, 95% of patients eat well; nearly 50% have required an anastomotic dilatation; troublesome regurgitation has been rare; and 4% have refractory postvagotomy dumping. CONCLUSIONS: Esophagectomy, preferably through a transhiatal approach, is generally safe and effective therapy in selected patients with achalasia. Unique technical considerations include difficulty encircling the dilated cervical esophagus, deviation of the esophagus into the right chest, large aortic esophageal arteries, and adherence of the exposed esophageal submucosa to the adjacent aorta after prior myotomy.

Transhiatal esophagectomy for treatment of benign and malignant esophageal disease.

Since our initial 1978 report, we have performed transhiatal esophagectomy (THE) in 1085 patients with intrathoracic esophageal disease: 285 (26%) benign lesions and 800 (74%) malignant lesions (4.5% upper, 22% middle, and 73.5% lower third/cardia). THE was possible in 97% of patients in whom it was attempted; reconstruction was performed at the same operation in all but six patients. The esophageal substitute was positioned in the original esophageal bed in 98%, stomach being used in 782 patients (96%) and colon in those with a prior gastric resection. Hospital mortality was 4%, with three deaths due to uncontrollable intraoperative hemorrhage. Major complications included anastomotic leak (13%), atelectasis/pneumonia prolonging hospitalization (2%), recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration (< 1% each). There were five reoperations for mediastinal bleeding within 24 hours of THE. Intraoperative blood loss averaged 689 ml. Altogether, 78% of the patients had no postoperative complications. Actuarial survival of the cancer patients mirrors that reported after transthoracic esophagectomy. Late functional results are good or excellent in 80%. Approximately 50% have required one or more anastomotic dilatations. With intensive preadmission pulmonary and physical conditioning, use of a side-to-side staple technique (which has reduced the cervical esophagogastric anastomotic leak rate to less than 3%), and postoperative epidural anesthesia, the need for an intensive care unit stay has been eliminated and the length of hospital stay was reduced to 7 days. We concluded that THE can be achieved in most patients requiring esophageal resection for benign and malignant disease and with greater safety and less morbidity than the traditional transthoracic approaches.

Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

Indomethacin-induced apoptosis in esophageal adenocarcinoma cells involves upregulation of Bax and translocation of mitochondrial cytochrome C independent of COX-2 expression.

The prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to exert a chemopreventive effect in esophageal and other gastrointestinal tumors. The precise mechanism by which this occurs, however, is unknown. While the inhibition of COX-2 as a potential explanation for this chemopreventive effect has gained a great deal of support, there also exists evidence supporting the presence of cyclooxygenase-independent pathways through which NSAIDs may exert their effects. In this study, immunohistochemical analysis of 29 Barrett's epithelial samples and 60 esophageal adenocarcinomas demonstrated abundant expression of the COX-2 protein in Barrett's epithelium, but marked heterogeneity of expression in esophageal adenocarcinomas. The three esophageal adenocarcinoma cell lines, Flo-1, Bic-1, and Seg-1, also demonstrated varying expression patterns for COX-1 and COX-2. Indomethacin induced apoptosis in all three cell lines, however, in both a time- and dose-dependent manner. In Flo-1 cells, which expressed almost undetectable levels of COX-1 and COX-2, and in Seg-1, which expressed significant levels of COX-1 and COX-2, indomethacin caused upregulation of the pro-apoptotic protein Bax. The upregulation of Bax was accompanied by the translocation of mitochondrial cytochrome c to the cytoplasm, and activation of caspase 9. Pre-treatment of both cell lines with the specific caspase 9 inhibitor, z-LEHD-FMK, as well as the broad-spectrum caspase inhibitor, z-VAD-FMK, blocked the effect of indomethacin-induced apoptosis. These data demonstrate that induction of apoptosis by indomethacin in esophageal adenocarcinoma cells is associated with the upregulation of Bax expression and mitochondrial cytochrome c translocation, and does not correlate with the expression of COX-2. This may have important implications for identifying new therapeutic targets in this deadly disease.

Content of thoracic residency training and its relevance to the practice of medicine.

BACKGROUND: The Thoracic Surgery Directors Association (TSDA) curriculum book provides learning objectives for a thoracic surgery residency. Our purpose was to evaluate the relevance of these objectives through feedback from recent graduates. METHODS: Graduates of multiple TSDA programs were mailed a 50-item questionnaire. Survey items were objectives from the TSDA curriculum book representing six areas of thoracic surgery. Graduates rated each objective for adequacy of instruction and relevance to their current practice on Likert-type scales. RESULTS: Two hundred twenty-eight surveys were included in the analysis. Despite excellent operating room education, graduates across subspecialty lines reported the need for improved education in "nonoperative" subjects. Graduates practicing cardiac surgery reported little relevance of their general thoracic educational experience. Conversely, graduates practicing general thoracic surgery expressed the need for more/better educational experiences in thoracic oncology and esophageal surgery. CONCLUSIONS: Contemporary thoracic surgical education can be improved. A strong need for improvement exists in the teaching of "nonoperative" subjects. As graduates elect careers in thoracic subspecialties, a need exists to align thoracic surgery educational experiences with ultimate career goals of residents.

A minimal critical region of the 8p22-23 amplicon in esophageal adenocarcinomas defined using sequence tagged site-amplification mapping and quantitative polymerase chain reaction includes the GATA-4 gene.

The incidence of esophageal adenocarcinomas has increased greatly over the past 20 years. The genetic alterations associated with this disease, however, remain largely unknown. We identified recently a novel amplicon at 8p22-23 in esophageal adenocarcinomas using the restriction landmark genomic scanning two-dimensional gel technique. Four known genes within or near this amplicon were initially characterized. The cathepsin B (CTSB) gene was found to be amplified in 13% of esophageal tumors. CTSB was shown previously to be overexpressed without amplification in many other human cancers. An approach termed sequence tagged site-amplification mapping has been implemented in the present study, allowing the 8p22-23 amplicon to be narrowed from 12 cM to a <2-cM minimal amplified area located between markers D8S552 and D8S1759. The CTSB gene maps within this region. To identify other cancer-related candidate genes in this region, a positional candidate gene approach was subsequently applied to characterize this minimal critical region. An expressed sequence tag (EST), which was included in the minimal critical region, demonstrated both amplification and overexpression. This EST and the extended sequence from the EST were determined to be a novel sequence in the 3' untranslated region of the human GATA-4 gene. GATA-4, a member of a zinc finger transcription factor family, was confirmed to be amplified and overexpressed in esophageal adenocarcinomas and was localized within <0.5 kb from CTSB. Furthermore, amplification of 8p22-23 was detected in one of eight gastric cardia adenocarcinomas but was not observed in either human lung adenocarcinomas (n = 39) or in esophageal squamous cell carcinomas (n = 24). The relatively high frequency of the 8p22-23 amplification in esophageal (13.6%) and gastric cardia (12.5%) adenocarcinomas may indicate a specificity of this amplicon for tumors of gastroesophageal origin.

Thoracic surgery training at the University of Michigan.

The process of thoracic surgery resident education is and always has been taken very seriously at the University of Michigan, where it is regarded as a key mission of the faculty. More attention is paid to the details of providing a supportive educational environment using established principles of education, curriculum planning, evaluation, and feedback. Resident education is the order of business today and, although challenged by the demands of managed care and cost containment, it remains among the most important priorities at the University of Michigan.

Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis.

BACKGROUND: Although the acute postoperative complications of a cervical esophagogastric anastomosis are less than those with an intrathoracic esophageal anastomosis, the long-term sequelae of a cervical anastomotic leak are not as minor as initially reported. Nearly 50% of cervical anastomotic leaks result in an anastomotic stricture, and the subsequent need for chronic dilatations negates the merits of an operation intended to restore comfortable swallowing. OBJECTIVE: This study was undertaken to determine whether construction of a side-to-side stapled cervical esophagogastric anastomosis after transhiatal esophagectomy could reliably eliminate the majority of anastomotic leaks. METHODS: In 114 consecutive patients undergoing transhiatal esophagectomy, a functional side-to-side cervical esophagogastric anastomosis was constructed with the Auto Suture Endo-GIA II stapler (United States Surgical Corporation, Auto Suture Company Division, Norwalk, Conn) applied directly through the cervical wound. This side-to-side stapled anastomosis has 3 rows of staples. Early postoperative anastomotic morbidity, subsequent need for anastomotic dilatations, and patient satisfaction with swallowing were evaluated. RESULTS: Before the side-to-side stapled anastomosis, the incidence of cervical esophagogastric anastomosis leak in over 1000 patients undergoing transhiatal esophagectomy having a manually sewn anastomosis varied from 10% to 15%. Among the 111 survivors of transhiatal esophagectomy and a side-to-side stapled anastomosis, there were 3 (2.7%) clinically significant anastomotic leaks. This lowered incidence of leaks has contributed to reduction in the average length of stay after an uncomplicated transhiatal esophagectomy to 7 days and has provided more comfortable swallowing, ease of subsequent esophageal dilatations, and greater patient satisfaction. CONCLUSIONS: Construction of the cervical esophagogastric anastomosis with a side-to-side stapled anastomosis greatly reduces the frequency of anastomotic leaks and later strictures. The side-to-side stapled anastomosis is a major technical advance in the progression of refinements of transhiatal esophagectomy and a cervical esophagogastric anastomosis.

Identification and characterization of a 19q12 amplicon in esophageal adenocarcinomas reveals cyclin E as the best candidate gene for this amplicon.

Genomic DNA amplification in tumors is frequently associated with an increased gene copy number of oncogenes or other cancer-related genes. We have used a two-dimensional whole-genome scanning technique to identify gene amplification events in esophageal adenocarcinomas. A multicopy genomic fragment from a tumor two-dimensional gel was cloned, and genomic amplification encompassing this fragment was confirmed by Southern blot analysis. The corresponding DNA sequence was matched by BLAST to a BAC contig, which allowed the use of electronic-PCR to localize this amplicon to 19q12. Sequence tagged site-amplification mapping, an approach recently implemented in our laboratory (Lin, L. et al., Cancer Res., 60: 1341-1347,2000), was used to characterize the amplicon. Genomic DNA from 65 esophageal and 11 gastric cardia adenocarcinomas were investigated for 19q12 amplification using quantitative PCR at 11 sequence tagged site markers neighboring the cloned fragment. The amplicon was narrowed from >8 cM to a minimal critical region spanning <0.8 cM, between D19S919 and D19S882. This region includes the cyclin E gene. Fourteen expressed sequence tags (ESTs) covering the minimal region were then assayed for potential gene overexpression using quantitative reverse transcription-PCR. Seven of the selected ESTs were found to be both amplified and overexpressed. Among these seven ESTs, cyclin E showed the highest frequency of gene amplification and overexpression in the tumors examined, which allowed us to finalize the core-amplified region to <300 kb. These results indicate that cyclin E is the likely target gene selected by the amplification event at 19q12. The fact that cyclin E overexpression was found only in the amplified tumors examined indicates that gene amplification underlies the cyclin E gene overexpression. Our study represents the first extensive analysis of the 19q12 amplicon, and is the first to physically map the core-amplified domain to a region of <300 kb that includes cyclin E. Amplification of 19q12 was found neither in the 28 esophageal squamous cancers nor in the 39 lung adenocarcinomas examined but was observed in 13.8% of esophageal and 9.1% of gastric cardia adenocarcinomas.

Transhiatal esophagectomy: clinical experience and refinements.

OBJECTIVE: To review the authors' clinical experience with transhiatal esophagectomy (THE) and the refinements in this procedure that have evolved. BACKGROUND: Increased use of THE during the past two decades has generated controversy about the merits and safety of this approach compared with transthoracic esophageal resection. The authors' large THE experience provides a valuable basis for benchmarking data regarding the procedure. METHODS: The results of THE were analyzed retrospectively using the authors' prospectively established esophageal resection database and follow-up information on these patients. RESULTS: From 1976 to 1998, THE was performed in 1085 patients, 26% with benign disease and 74% with cancer. The procedure was possible in 98.6% of cases. Stomach was the esophageal substitute in 96%. The hospital mortality rate was 4%. Blood loss averaged 689 cc. Major complications were anastomotic leak (13%), atelectasis/pneumonia (2%), intrathoracic hemorrhage, recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration (<1% each). Actuarial survival of patients with carcinoma equaled or exceeded that reported after transthoracic esophagectomy. Late functional results were good or excellent in 70%. With preoperative pulmonary and physical conditioning, a side-to-side stapled cervical esophagogastric anastomosis (<3% incidence of leak), and postoperative epidural anesthesia, the need for an intensive care unit stay has been eliminated and the length of stay reduced to 7 days. CONCLUSION: THE is possible in most patients requiring esophageal resection and can be performed with greater safety and fewer complications than the traditional transthoracic approaches.

Epidural abscess: a delayed complication of esophageal stenting for benign stricture.

A case of anterior cervical epidural abscess associated with perforation of an endoscopically placed esophageal stent is presented. Although delayed esophageal perforation is a known complication of endoscopic stenting, no cases presenting with epidural abscess have yet been reported. The increasing application of endoscopic stenting for benign esophageal strictures provides greater opportunity for this type of delayed complication.

Detection of erbB-2 amplifications in tumors and sera from esophageal carcinoma patients.

We used TaqMan PCR to detect quantitative anomalies of tumor markers in both tumor and serum DNA from esophageal cancer patients. We demonstrated the potential of this methodology by detecting erbB-2 amplifications in a plurality of esophageal tumor samples. These amplifications were corroborated by Southern blots. We then showed the potential of this methodology to detect quantitative anomalies of erbB-2 in serum DNA from individuals with a corresponding amplification in the tumor. The capability of TaqMan PCR to detect abnormalities in serum of esophageal cancer patients creates an opportunity to diagnose esophageal cancer and to monitor the outcome of treatment with a blood test.