Delineation of disease phenotypes associated with esophageal adenocarcinoma by MALDI-IMS-MS analysis of serum N-linked glycans.

N-Linked glycans, extracted from patient sera and healthy control individuals, are analyzed by Matrix-assisted laser desorption ionization (MALDI) in combination with ion mobility spectrometry (IMS), mass spectrometry (MS) and pattern recognition methods. MALDI-IMS-MS data were collected in duplicate for 58 serum samples obtained from individuals diagnosed with Barrett's esophagus (BE, 14 patients), high-grade dysplasia (HGD, 7 patients), esophageal adenocarcinoma (EAC, 20 patients) and disease-free control (NC, 17 individuals). A combined mobility distribution of 9 N-linked glycans is established for 90 MALDI-IMS-MS spectra (training set) and analyzed using a genetic algorithm for feature selection and classification. Two models for phenotype delineation are subsequently developed and as a result, the four phenotypes (BE, HGD, EAC and NC) are unequivocally differentiated. Next, the two models are tested against 26 blind measurements. Interestingly, these models allowed for the correct phenotype prediction of as many as 20 blinds. Although applied to a limited number of blind samples, this methodology appears promising as a means of discovering molecules from serum that may have capabilities as markers of disease.

Ion mobility-mass spectrometry analysis of serum N-linked glycans from esophageal adenocarcinoma phenotypes.

Three disease phenotypes, Barrett's esophagus (BE), high-grade dysplasia (HGD), esophageal adenocarcinoma (EAC), and a set of normal control (NC) serum samples are examined using a combination of ion mobility spectrometry (IMS), mass spectrometry (MS), and principal component analysis (PCA) techniques. Samples from a total of 136 individuals were examined, including 7 characterized as BE, 12 as HGD, 56 as EAC, and 61 as NC. In typical data sets, it was possible to assign ∼20 to 30 glycan ions based on MS measurements. Ion mobility distributions for these ions show multiple features. In some cases, such as the [S1H5N4+3Na]3+ and [S1F1H5N4+3Na]3+ glycan ions, the ratio of intensities of high-mobility features to low-mobility features vary significantly for different groups. The degree to which such variations in mobility profiles can be used to distinguish phenotypes is evaluated for 11 N-linked glycan ions. An outlier analysis on each sample class followed by an unsupervised PCA using a genetic algorithm for pattern recognition reveals that EAC samples are separated from NC samples based on 46 features originating from the 11-glycan composite IMS distribution.

Survival outcomes of resected patients who demonstrate a pathologic complete response after neoadjuvant chemoradiation therapy for locally advanced esophageal cancer.

A variety of strategies, using chemotherapy, radiation therapy, and surgical resection have been employed in the treatment of locally advanced esophageal cancer. No strategy has proven superior, and poor long-term survival is anticipated. A survival benefit has been suggested for patients who achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation therapy. We examined the collective results at three institutions of patients who achieved a pCR following neoadjuvant chemoradiation therapy. A retrospective, chart-based review was conducted. Kaplan-Meier calculations were used to determine overall and disease-free survival. Between 1995 and 2002, 229 patients were treated with neoadjuvant chemoradiation followed by surgery as a planned approach for locally advanced esophageal cancer. Forty-one patients (18%) demonstrated pCR and were the focus of this study. Histology was adenocarcinoma in 29, squamous in 10, and adenosquamous/undifferentiated in two patients. Forty patients were staged by endoscopic ultrasound prior to neoadjuvant therapy and all demonstrated a T-stage of 2 or higher, while 19 had evidence of nodal metastasis. Four patients died in the perioperative period. The remaining patients have been followed for an average of 46 months. Overall survival at 5 years was 56.4% and a median survival has not been reached. Esophageal cancer patients who demonstrate a pCR following neoadjuvant chemoradiation are a select subset who demonstrate excellent long-term survival. Identification of clinical variables or biomarkers predictive of pCR may therefore optimize treatment strategies of patients with locally advanced esophageal cancer.

The current role of mediastinoscopy in the evaluation of thoracic disease.

OBJECTIVE: Mediastinoscopy is a common procedure used for the diagnosis of thoracic disease and the staging of lung cancer. We sought to determine the current role of mediastinoscopy in the evaluation of thoracic disease. METHODS: We conducted a retrospective review of all mediastinoscopies performed by members of our service between January 1988 and September 1998. RESULTS: We performed mediastinoscopies on 2137 patients. A total of 1745 patients underwent mediastinoscopy for known or suspected lung cancer. In 422 of these procedures, N2 or N3 disease was identified; only 28 of these patients underwent resection. The remaining 1323 had no evidence of metastatic disease. In these patients 947 had lung cancer. Only 76 of the patients with lung cancer were found to have N2 disease at exploration. Among the 1323 patients with a negative mediastinoscopy result, 52 underwent resection of a nonbronchogenic malignancy, and 217 had resection of a benign lesion. A total of 392 patients underwent mediastinoscopy for the evaluation of mediastinal adenopathy in the absence of any identifiable pulmonary lesion. Of these, 161 had a nonbronchogenic malignancy, 209 had benign disease, and 25 had no diagnosis established; mediastinoscopy established a definitive diagnosis in 93.6% of patients. In the entire group of 2137 patients, there were 4 perioperative deaths and 12 complications. Only one death was directly attributed to mediastinoscopy. No deaths or complications occurred in patients undergoing mediastinoscopy for benign disease. CONCLUSIONS: Mediastinoscopy is a highly effective and safe procedure. We believe that mediastinoscopy should currently be used routinely in the diagnosis and staging of thoracic diseases.

Allelotype analysis of esophageal adenocarcinomas: evidence for the involvement of sequences on the long arm of chromosome 4.

The incidence of esophageal adenocarcinoma has increased dramatically over the past 20 years. The causes for this change in incidence and the genetic defects that underlie tumorigenesis are unknown. We performed loss of heterozygosity (LOH) studies in esophageal adenocarcinomas in an effort to map the location of tumor suppressor genes involved in the initiation or progression of this cancer. A genome-wide search for LOH was undertaken using microsatellite repeat polymorphisms and a panel of 27 tumor and matched normal DNAs. This is the first report of an allelotype analysis of esophageal adenocarcinomas. We observed frequent loss of sequences on the short arm of chromosome 17 in the region of the TP53 gene. We also identified a region on 4q lost in more than half of the tumors investigated. The high rate of LOH for 4q sequences speaks to the involvement of an as yet unidentified tumor suppressor gene in esophageal adenocarcinoma tumorigenesis.