Search

Cytochrome P450 epoxygenases (CYP450) have been recently shown to promote malignant progression. Here we investigated the mRNA and protein expression and potential clinical relevance of CYP2C9 in esophageal cancer. Highest expression was detected in esophageal adenocarcinoma (EAC; n=78) and adjacent esophageal mucosa (NEM; n=79). Levels of CYP2C9 in EAC and NEM were significantly higher compared to esophageal squamous cell carcinoma (ESCC; n=105). Early tumor stages and well-differentiated tumors showed a significantly higher CYP2C9 expression compared to progressed tumors. Moreover, CYP2C9 expression was correlated to high Ki-67 labeling indices in EAC and Ki-67 positive tumor cells in EAC and ESCC. Selective inhibition of CYP2C9 decreased tumor cell proliferation (KYSE30, PT1590 and OE19) in vitro, which was abolished by 11,12-epoxyeicosatrienoic acid (11,12-EET). Cell-cycle analysis using FACS revealed that inhibition of CYP2C9 leads to a G0/G1 phase cell-cycle arrest. CYP2C9 seems to be relevant for early esophageal cancer development by promoting tumor cell proliferation. Pharmacological inhibition of CYP2C9 might contribute to a more efficient therapy in CYP2C9 highly expressing esophageal cancers., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: To evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies., Methods: The Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up., Results: Ep-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor., Conclusion: Our results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention.

We have shown previously that microsatellite alterations in serum DNA was predictive of distant metastasis in a study with 21 primary head and neck squamous cell carcinoma patients. To further investigate serum microsatellite alterations as a prognostic tool, we carried out microsatellite analysis of serum DNA with 10 markers on 152 patients with head and neck cancer. Forty-five percent (68/152) of patients had microsatellite alterations of serum DNA identical to corresponding tumor DNA. In 16 patients that had distant metastasis, 11 patients had a positive serum test (microsatellite alterations detectable in their serum DNA with one or more markers). The difference in distant metastasis rates between the negative and positive serum tests (6.0% [5/84] vs. 16.2% [11/68], RR = 2.7) was clinically significant and almost reached statistical significance (p = 0.06). When the analysis was restricted to patients with recurrent disease, a positive serum test correlated with those who developed distant metastasis (p = 0.04). Other parameters, such as development of recurrence, stage of the cancer, disease-free survival and overall survival, were not associated with a positive serum test. Detecting tumor DNA in serum by microsatellite analysis may help identify patients at risk for distant metastasis. Therefore, circulating tumor cells may contribute to the presence of tumor DNA in the serum. In the future if a serum test is positive, therapeutic approaches may by intensified, such as platinum-based chemoradiation, to reduce distant failures., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: Esophageal squamous cell cancer can be treated effectively by potentially curative surgery if diagnosed at an early stage. Our aim was to develop a novel molecular approach as a noninvasive test for squamous cell cancer detection and as an indicator for the prognosis of the patients., Experimental Design: Matched normal, tumor, and serum samples were obtained from 28 patients with squamous cell carcinoma (SCC) of the esophagus. DNA was extracted, and the samples were subjected to microsatellite analysis using 12 markers. Serum and normal DNA from 10 healthy individuals served as controls., Results: Twenty-six of the 28 patients (92.9%) with SCC were found to have one or more microsatellite DNA alterations in their primary tumor. Twenty-seven of the 28 patients (96.4%) had at least one alteration in the serum by microsatellite analysis. Mean age was 61.5 years. Microsatellite alterations were not identified in the serum DNA of samples from normal control subjects. Median follow-up was 13 months. Survival and recurrence were not significantly correlated with either loss of heterozygosity in the tumor or in the serum., Conclusions: Microsatellite DNA analysis of tumor and serum specimen is a potentially valuable tool for detection and for the evaluation of the prognosis of SCC of the esophagus. The follow-up in our study is still too short to draw final conclusions on the correlation of disease-specific survival and disease recurrence with microsatellite alterations. The evidence of circulating tumor DNA in almost all of our patients underlines a systemic component of the disease that is not surgically amenable.

Prompt detection of head and neck squamous cell carcinoma (HNSCC) is vital to successful patient management. In this feasibility study, we used microsatellite analysis to detect tumor-specific genetic alterations in exfoliated oral mucosal cell samples from patients with known cancer. Exfoliated mucosal cells in pretreatment oral rinse and swab samples were collected from 44 HNSCC patients and from 43 healthy control subjects (20 nonsmokers and 23 smokers). We tested a panel of 23 informative microsatellite markers to assay DNA from the matched lymphocyte, tumor (from cancer cases), and oral test samples. Loss of heterozygosity or microsatellite instability of at least one marker was detected in 38 (86%) of 44 primary tumors. Identical alterations were found in the saliva samples in 35 of these 38 cases (92% of those with markers; 79% overall) including 12 of 13 cases with small primaries [stage Tt or Tx (occult primary)] and 4 of 4 cases of patients that had undergone prior radiation. Microsatellite instability was detectable in the saliva in 24 (96%) of 25 cases in which it was present in the tumor, and loss of heterozygosity was identified in the test sample in 19 (61%) of 31 cases. No microsatellite alterations were detected in any of the samples from the healthy control subjects. This approach must now be refined and validated for the detection of clinically occult disease. Microsatellite analysis of oral samples may then become a valuable method for detecting and monitoring HNSCC.

Zenker's diverticulum is a common anomaly in the elderly patient. Carcinoma in such a diverticulum is a rare but recognized complication of a posterior pharyngeal pulsion diverticulum. We present a case of a 67-year-old patient with a long-standing symptomatic Zenker's diverticulum. The diagnosis of the neoplasm was only achieved intraoperatively. The patient underwent a proximal esophageal resection with lymphadenectomy. Reconstruction was done with a microvascular free jejunal transplant. The postoperative course was uneventful. Wide oncologic surgical resection is the therapy of choice in cases of carcinoma in a Zenker's diverticulum.

Objective: To more clearly define the frequency and the regions of chromosome arm 4q loss in head and neck squamous cell carcinoma., Design: A retrospective microsatellite analysis of DNA from previously microdissected primary tumor samples., Setting: Academic medical center., Patients and Methods: One hundred primary tumor samples from patients with head and neck squamous cell carcinoma were analyzed for loss of heterozygosity on the long arm of chromosome 4. The Kaplan-Meier method was used to estimate survival for 97 patients for whom clinical data were available. The Cox proportional hazards model was used to compare survival, and logistic regression was used to search for associations between clinical tumor characteristics and 4q status., Results: Analysis of 33 polymorphic microsatellite markers identified 51 samples (51%) exhibiting loss of heterozygosity of 4q in at least 1 locus. Eighteen tumors revealed loss at all informative markers, indicating monosomy or complete deletion of 4q. Thirty-three tumors displayed partial loss of heterozygosity and delineated 2 minimal areas of loss at 4q2324 and 4q2829. Eleven tumors displayed loss solely at the 4q2324 region, 13 tumors displayed deletions confined to the 4q2829 region, and 9 tumors displayed selective loss at both regions. A separate analysis in a subset of 94 primary head and neck tumors was done to further delineate the minimal area of chromosomal loss at 4q2324. Analysis of 8 markers in this region allowed us to identify the smallest region of loss between markers D4S2986 and D4S1564 (a distance of 2 centimorgans). Review of the clinical records of 97 patients revealed no statistically significant association between 4q status and any clinical variable, including survival., Conclusion: These results confirm a high frequency of chromosome arm 4q loss in primary head and neck squamous cell carcinoma and might demarcate 2 novel putative suppressor loci involved in progression of this carcinoma.

Patients with squamous cell carcinoma of the head and neck (HNSCC) often develop second carcinomas elsewhere in the upper aerodigestive tract. Some of these paired tumors share a common origin, reflecting the ability of a single progenitor cell to replicate, expand, and populate contiguous regions of the upper aerodigestive tract-a process referred to as clonal expansion. The geographical limitations of clonal expansion, however, have not been adequately addressed. For example, it is not known whether a neoplastic clone from the oral cavity, pharynx, or larynx can migrate to the esophagus. We compared paired tumors from 16 patients with HNSCC and a second squamous cell carcinoma of the esophagus (ESCC) for patterns of allelic loss on chromosomal arms 3p, 9p, and 17p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. In 14 cases (87%), the paired tumors had discordant patterns of allelic loss, suggesting that these tumors were not clonally related. Conversely, two (13%) of the 16 paired tumors had identical genetic alterations, which suggests clonal expansion as the mechanism underlying tumor multifocality. One clone spread from the hypopharynx into the cervical esophagus, and the other spread from the tonsil to the distal esophagus. Although most second ESCCs appear to arise as independent neoplasms, a clonal population of neoplastic cells is capable of traveling across substantial distances to give rise to second tumors at different anatomical sites.