The integrins are a family of heterodimeric transmembrane signaling receptors that mediate the adhesive properties of epithelial cells affecting cell growth and differentiation. In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis. However, only few studies have investigated the role of integrin expression in esophageal squamous cell carcinoma (ESCC). Using a novel quantifying immunofluorescence-staining assay, we investigated the expression of the integrins α2β1, α3β1, α6β1, and α6β4 in primary ESCC of 36 patients who underwent surgical resection. Magnitude and distribution of expression were analyzed in primary tumor samples and autologous esophageal squamous epithelium. The persistence of the physiologically polarized expression of the subunits α6, β1, and β4 in the tumor tissue was significantly associated with prolonged relapse-free survival (p = 0.028, p = 0.034, p = 0.006). In contrast, patients with reduced focal α6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong α6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001). Multivariate regression analysis identified the maintenance of strong α6 immunoreactivity at the invasion front as an independent prognostic factor for increased relapse-free and disease-specific survival (p = 0.003; p = 0.003). Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients. Particularly, the distinct expression of the integrins α6β4 and α6β1 at the invasion front as well as the maintenance of a polarized integrin expression pattern in the tumor tissue may serve as valuable new markers to assess the aggressiveness of ESCC.

Die umfassende genetische und phänotypische Analyse disseminierter Tumorzellen, unter denen sich potentielle Vorläufer späterer Metastasen befinden, stellt in vivo nicht zuletzt aufgrund ihrer Seltenheit weiterhin eine große Herausforderung dar. Zum besseren Verständnis der grundlegenden Mechanismen zur Metastasierung solider Tumoren haben wir ein Tumor-Xenograft-Modell in der SCID-Maus etabliert, welches die Isolierung disseminierter Tumoreinzelzellen erlaubt.

The aim of the present study was to identify differentially expressed genes and their related biological pathways in the secretory phase endometrium from patients with recurrent miscarriage (RM) and fertile subjects. Endometrial samples from RM and fertile patients were analyzed using the Affymetrix GeneChip® ST Array. The bioinformatic analysis using the Partek Genomic Suite revealed 346 genes that were differentially expressed (175 up-regulated and 171 down-regulated) in the endometrium of RM patients compared to the fertile subjects (fold change ≥1.5, p<0.005). Validation step using quantitative real-time polymerase chain reaction (qPCR) confirmed a similar expression pattern of four exemplary genes: one up-regulated gene (fibroblast growth factor 9, FGF9) and three down-regulated genes: integrin β3 (ITGB3), colony stimulating factor 1 (CSF1) and matrix-metalloproteinases 19 (MMP19). The Gene Set Enrichment Analysis (GSEA) and the Pathway Studio Software have found 101 signaling pathways (p<0.05) associated with the affected genes including the FGFR3/signal transducer and activator of transcription (STAT) pathway and the CSF1R/STAT pathway. Cell adhesion, cell differentiation and angiogenesis were among biological processes indicated by this system. In conclusion, microarray technique is a useful tool to study gene expression in the secretory phase-endometrium of RM patients. The differences in endometrial gene expressions between healthy and RM subjects contribute to an increase in our knowledge on molecular mechanisms of RM development and may improve the outcome of pregnancies in high-risk women with RM.

BACKGROUND AND AIMS:In gastric cancer, regional lymph node metastasis verified by histopathological examination is the most important prognostic factor after complete surgical tumor resection (R0). However, the prognostic value of immunohistochemically identifiable disseminated tumor cells in lymph nodes without histopathological tumor burden in patients with gastric cancer is still controversially discussed. The aim of the study was to assess the frequency and prognostic impact of minimal tumor cell spread to lymph nodes in these patients.PATIENTS-METHODS:One hundred sixty lymph nodes judged as "tumor free" on routine histopathology obtained from 58 patients with gastric adenocarcinoma were analyzed immunohistochemically using the monoclonal anti-EpCAM antibody Ber-EP4 for occult disseminated tumor cells.RESULTS:Tumor cells in lymph nodes were detected in 62 (38.8%) of the 160 "tumor-free" lymph nodes obtained from 39 (67.2%) patients. Multivariate Cox regression analysis confirmed the presence of disseminated tumor cells in "tumor-free" lymph nodes as an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.008) and overall survival (p = 0.009).CONCLUSIONS:The frequent occurrence and prognostic impact of minimal disseminated tumor cells in lymph nodes of patients with gastric carcinoma support the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination.

Background and aims Occurrence of tumor relapse is frequent in patients with pancreatic cancer despite the absence of residual tumor detectable at primary surgery and in histopathological examination. Therefore, it has to be assumed that current tumor staging procedures fail to identify minimal amounts of disseminated tumor cells, which might be precursors of subsequent metastatic relapse. The aim of this study was to assess the prognostic impact of minimal tumor cell spread detected in lymph nodes classified as "tumor-free" in routine histopathologic evaluation.Materials and methods A total of 154 "tumor-free" lymph nodes from 59 patients with pancreatic cancer who underwent intentionally curative tumor resection were examined by immunohistochemistry for disseminated tumor cells.Results Fifty (32.5%) of the "tumor-free" lymph nodes obtained from 36 (61%) patients displayed disseminated tumor cells. Multivariate survival analysis revealed that the presence of disseminated tumor cells in "tumor-free" lymph nodes is an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.03) and overall survival (p = 0.02).Conclusions The frequent occurrence and prognostic impact of immunohistochemically identifiable disseminated tumor cells in lymph nodes of patients with operable pancreatic cancer supports the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination.

The increasing use of primary tumors as surrogate markers for prognosis and therapeutic decisions neglects evolutionary aspects of cancer progression. To address this problem, we studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers and prospectively analyzed single disseminated cancer cells from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients. Whole-genome screening revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. However, we identified chromosome 17q12–21, the region comprising HER2, as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death.

BACKGROUND:Occurrence of tumor relapse is frequent in patients with carcinoma of the papilla of Vater despite the absence of residual tumor detectable at primary surgery. Therefore it has to be assumed that current tumor staging procedures fail to identify minimal amounts of tumor cells disseminated to secondary organs, which might be precursors of subsequent metastatic relapse. The aim of the study was to assess the frequency and prognostic impact of minimal tumor cell spread in lymph nodes classified as 'tumor-free' in routine histopathologic evaluation.MATERIALS AND METHODS:A total of 41 'tumor-free' lymph nodes from 23 patients with adenocarcinoma of the papilla of Vater who underwent curative tumor resection (R0) were examined by immunohistochemistry with the monoclonal anti-EpCAM antibody Ber-EP4 for minimal disseminated tumor cells.RESULTS:Twelve (29.3%) of the 41 'tumor-free' lymph nodes obtained from 9 (39.1%) of the 23 patients displayed EpCAM-positive cells. Kaplan-Meier survival analysis revealed that patients with EpCAM-positive cells in lymph showed a clearly reduced relapse-free and overall survival compared with patients without such cells. However, these differences were not statistically significant (p = 0.13 for relapse-free survival, p = 0.11 for overall survival).DISCUSSION:Immunohistochemical assessment may refine the staging of resected lymph nodes in patients with carcinoma of the papilla of Vater. However, the presence of minimal disseminated tumor cells in lymph nodes had no significant impact on the prognosis in these patients.

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HYPOTHESIS Patients with pulmonary metastatic soft tissue sarcoma benefit from resection, with long-term cure possible. DESIGN Retrospective medical records review. SETTING Academic tertiary care center. PATIENTS Between January 1, 1991, and December 31, 2002, 61 patients (33 men and 28 women; median age at initial diagnosis, 42 years [age range, 18-74 years]) were surgically treated for pulmonary metastases of soft tissue sarcoma at University Hospital, Hamburg-Eppendorf, Germany. INTERVENTIONS Sternotomy or anterior lateral thoracotomy was performed for metastasectomy, including wedge resection or lobectomy. MAIN OUTCOME MEASURE The effects of clinical and pathologic factors on disease-specific survival were analyzed using the log rank test and a multivariate Cox proportional hazards model. RESULTS Primary tumor size was pT1 in 13 patients and pT2 in 48 patients. The differentiation was high in 7 patients, intermediate in 19 patients, and low in 35 patients. The mean number of resected pulmonary metastatic lesions was 5 (range, 1-48). An anterolateral thoracotomy was performed in 39 patients, and sternotomy in 22 patients. There were no significant postoperative complications that required surgical revision. The perioperative mortality was 0%. At a mean follow-up of 60 months, the mean survival time after metastasectomy was 33 months (range, 2-125 months). The 5-year survival was 25%. The number of resected lung metastatic lesions had no prognostic relevance (P = .37). CONCLUSIONS Patients with lung metastasis from soft tissue sarcomas benefit from surgical excision. This treatment has low complication rates and has a favorable influence on the course of the disease. Long-term survival is possible even when recurrent pulmonary disease is resected.

Ähnlich wie bei anderen Karzinomen lassen sich Modulationen bei der Integrin-Expression auch beim ESCC häufig nachweisen, wobei insbesondere die Integrin-Untereinheiten α6, β1 und β4 bei der Progression des ESCC eine Rolle zu spielen scheinen. Darüber hinaus war die reduzierte Expression von α6 in der multivariaten Analyse mit einem signifikant verkürzten rezidivfreien Überleben korreliert.

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.

Stoecklein, Nikolas H.; Siegmund, Annika; Scheunemann, Peter; Luebke, Andreas M.; Erbersdobler, Andreas; Verde, Pablo E.; Eisenberger, Claus F.; Peiper, Matthias; Rehders, Alexander; Schulte Esch, Jan am; Trudo Knoefel, Wolfram; Hosch, Stefan B. Author Information

Einleitung: Trotz verbesserter operativer Techniken und multimodaler Therapiekonzepte konnte die Prognose von Patienten mit resektablen Papillenkarzinomen in den letzten Jahrzehnten nur unwesentlich verbessert werden. Das frühe und häufige Auftreten von Tumorrezidiven impliziert eine mit herkömmlichen Untersuchungstechniken schwer zu verifizierende okkulte minimale Tumorzellaussaat, welche jedoch mit sensitiven immunhistochemischen Methoden nachgewiesen werden kann.

BACKGROUND AND AIMS:Organ-confined oesophageal cancer in an early stage can be cured in many patients, whereas more extensive lesions have a poor prognosis. We sought to develop a non-invasive test for cancer detection and evaluation of the prognosis of the patients by using a novel molecular approach.MATERIAL AND METHODS:Matched normal-, tumour- and serum-samples were obtained from 32 patients with adenocarcinoma of the oesophagus. DNA was extracted and the samples were subjected to microsatellite analysis using 12 markers. Serum and normal samples from 10 healthy individuals served as controls.RESULTS:Twenty-seven of the 32 patients (84.4%) with malignant tumours were found to have one or more microsatellite DNA alterations in their primary tumour. Twenty-six of the 32 patients (81.3%) had alterations in the serum by microsatellite analysis. Interestingly, all patients without lymphatic metastasis and three early carcinomas (pT1pN0) already displayed LOH alteration in the serum, while all serum DNA of samples from normal control subjects were negative. Survival was not significantly correlated with either LOH in the tumour or LOH in the serum.CONCLUSION:These data suggest that microsatellite DNA analysis in serum specimens might provide a potentially valuable tool for early detection of oesophageal cancer. The evidence of circulating tumour DNA reflects the propensity of these tumours to spread to distant sites. Up to now the follow-up is still too short to draw further conclusions on the prognostic impact of this finding.

The integrins, a family of heterodimeric transmembrane receptor proteins, mediate cell-to-cell and cell-to-extracellular matrix (ECM) adhesive interactions and transduce signals from the ECM to the cell interior. Their contributions to tissue integrity and cell migration as well as their influence on cell growth and differentiation imply a role for integrins in tumour progression and metastasis. Solid tumours frequently present with altered integrin expression patterns and often prognosis is related to aberrant expression. However, until now little is known about the integrin expression in esophageal squamous cell carcinoma (ESCC). We therefore investigated the expression of integrin subunits α2, α3, α6, β1, and β4 in 36 patients with ESCC using an immunofluorescence staining assay. Quantity and distribution of integrin expression in tumor samples were analyzed and compared to integrin expression in normal corresponding esophageal mucosa. In normal esophageal epithelium α6 and β4 expression was notably strengthened along the basement membrane. A similar expression pattern was observed in more than 90 % of the tumor samples, where α6 and β4 were predominantly expressed at the invasive tumor front. Thereby, patients with reduced focal α6 expression had a significantly reduced relapse-free survival compared to patients with strong α6 expression (p < 0.005). Furthermore, strong β1 expression at the tumor invasion front was associated with absence of lymph node metastasis (pN0) (p < 0.02). In addition, patients whose primary tumors maintained a polarized integrin expression as observed in normal esophageal mucosa tended towards a favourable prognosis compared to patients with aberrant integrin expression patterns. Polarized expression of the integrin subunits α6 and β4 was significantly associated with a prolonged relapse-free survival (p < 0.05). However, only strong focal α6 expression could be confirmed as an independent prognostic factor for an increased relapse-free survival in the multivariate analysis. In conclusion, these findings are consistent with the hypothesis that in squamous cell carcinoma both alterations in pattern and quantity of integrin expression may affect disease progression and patient survival. The focal expression of integrin α6β4 at the invasive tumor front may represent an additional factor to assess the aggressiveness of ESCC.

Background: Skip metastasis to mediastinal lymph nodes is a prognostic factor for patients with non- small cell lung carcinoma. However, little is known about a noncontinuous nodal tumor cell spread in esophageal or cardial carcinoma. This issue is important to determine the extent of lymphadenectomy for esohageal and gastric resection. Methods: In a prospective study, a total of 6271 resected lymph nodes were obtained from 301 patients with resected carcinoma of the esophagus (n = 219) or the cardia (n = 82) and analysed by routine histopathology. In addition, 1230 of these lymph nodes classified as »umor-free« by routine histopathology harvested from 242 of these patients were screened for occult disseminated tumor cells by immunohistochemistry using the monoclonal antibody Ber-EP4. All lymph nodes were mapped according to the mapping scheme of the American Thoracic Society modified by Casson et al. [2]. Furthermore, bone marrow aspirates obtained from 192 of these patients were immunocytochemically analysed for isolated tumor cells using the anticytokeratin antibody A45B/B3. Results: 192 patients (64%) had pN1 disease, and 138 patients (57%) harbored occult disseminated tumor cells detected by immunohistochemistry. Isolated tumor cells in bone marrow were detected in 45 patients (23%) by immunocytochemistry.