Urs Metzger

High Ep-CAM Expression is Associated with Poor Prognosis in Node-positive Breast Cancer

Previous studies in small series of patients with invasive breast cancer suggested a prognostic value of Ep-CAM overexpression in primary tumor tissue. To corroborate these findings, we performed a retrospective analysis of Ep-CAM expression using a tissue microarray containing tissue specimens from a large patient set. Ep-CAM expression was evaluated by immunohistochemistry in breast cancer tissue from 1715 patients with documented raw survival data. High level Ep-CAM expression (overexpression) was found in 41.7% of tumor samples, low level expression was found in 48.0% and no expression in 10.3% of tumor samples. Ep-CAM expression predicted poor overall survival in this patient cohort (p < 0.0001). Overall survival decreased significantly with increasing Ep-CAM expression. However, in this patient sample Ep-CAM expression was not an independent prognostic marker by multivariate analysis. Subgroup analysis revealed that Ep-CAM expression was a prognostic marker in node-positive (p < 0.0001) but not in node-negative (p= 0.58) breast cancer patients. Intriguingly, Ep-CAM expression was predictive for a dismal prognosis in patients receiving adjuvant cytotoxic (p= 0.03) or hormonal therapy (p < 0.0001) but not in untreated patients (p= 0.41). In summary, this study provides strong evidence that expression of Ep-CAM is a powerful marker of poor prognosis in node-positive invasive breast carcinoma and a potential predictive marker of sensitivity to adjuvant hormonal and/or cytotoxic treatment modalities.

Expression of CEACAM6 in Resectable Colorectal Cancer: A Factor of Independent Prognostic Significance

PURPOSE CEACAM6, CEACAM1, and human carcinoembryonic antigen (CEA) are coexpressed in normal colorectal epithelia, but show deregulated expression in colorectal cancers (CRC). Upregulation of CEACAM6 expression in hyperplastic polyps and early adenomas represents one of the earliest observable molecular events leading to colorectal tumors. The aim of our study was to evaluate the prognostic relevance of CEACAM6, CEACAM1, and CEA tissue expression in patients with CRC. PATIENTS AND METHODS Immunohistochemical analysis was carried out on tissue microarrays from 243 paraffin-embedded biopsies from a randomized controlled clinical trial (Swiss Group for Clinical Cancer Research [SAKK] 40/81) of adjuvant fluorouracil-based chemotherapy with CEACAM-specific monoclonal antibodies. The median follow-up was 8 years. Overall survival (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier estimates and hazard ratios (HRs) estimated using Cox proportional hazards models. RESULTS Tissue expression of CEACAM6, CEACAM1, and CEA was enhanced in 55%, 58%, and 94% of patients, respectively. Multivariate Cox analysis including sex, age, tumor site, stage, differentiation grade, treatment, and nodal status as covariates showed that CEACAM6 overexpression independently predicted poor OS (HR, 1.86; P =.0100) and DFS (HR, 2.00; P =.0028), whereas CEACAM1 or CEA were not significantly related to these outcomes. The data did not provide evidence for or against the hypothesis that the CEACAM6 effect on survival differs according to treatment. CONCLUSION Expression of the cell adhesion molecule CEACAM6 in CRC is an independent prognostic factor allowing subdivision of patients into low- and high-risk groups. Whether CEACAM6 or CEA and CEACAM1 might be useful as predictive markers of chemotherapy benefit remains unclear.

Primary anastomosis vs Hartmann’s procedure in patients undergoing emergency left colectomy for perforated diverticulitis

Objective  Comparison of primary anastomosis (PA) and Hartmann’s procedure (HP) in perforated diverticulitis is biased as the patient groups are different in age, comorbidity and severity of disease. Still, PA has been advocated as the procedure of choice. The aim of this study was to compare the two surgical procedures after eliminating this selection bias using a propensity score model.

Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7

Deletions of chromosome band 18q21 appear with very high frequency in a variety of carcinomas, especially in colorectal cancer. Potent tumor suppressor genes located in this region encode transforming growth factor β (TGF‐β) signal transducers SMAD2 and SMAD4, and inactivation of either one leads to impaired TGF‐β‐mediated cell growth/apoptosis. Following the assignment of SMAD7 to 18q21, we first refined the SMAD7 gene position within this region by genetically mapping SMAD7 between SMAD2 and SMAD4. Further, to compare the respective frequencies of genetic alterations of these three SMAD genes in colorectal cancer, we undertook a large‐scale evaluation of the copy status of each of these genes on DNA samples from colorectal tumor biopsy material. Among a subset of 233 DNA samples for which data were available for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed high deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was deleted in only 48% of the tumors. Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4–7%). Compiled data for SMAD genes in each tumor show that the most common combination (26% of all the tumors) consists of the simultaneous deletions of SMAD2 and SMAD4 associated with normal diploidy or even duplication of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF‐β signaling, we hypothesize that the tumor might not benefit from simultaneous SMAD7 inactivation, thereby exerting selective pressure to retain or even to duplicate the SMAD7 gene.

Endosonographic radial tumor thickness after neoadjuvant chemoradiation therapy to predict response and survival in patients with locally advanced esophageal cancer: a prospective multicenter phase ll study by the Swiss Group for Clinical Cancer Research (SAKK 75/02)

BACKGROUND EUS response assessment in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation therapy (CRT) is limited by disintegration of the involved anatomic structures. OBJECTIVE Predictive and prognostic values of a prospectively defined maximum tumor thickness (MTT). DESIGN Prospective open-label phase ll study (SAKK 75/02). SETTING Multicenter, nationwide. PATIENTS Of 66 patients with primary CRT, 56 underwent en bloc esophagectomy. INTERVENTIONS EUS-measured MTT before and 2-5 weeks after CRT (yMTT). MAIN OUTCOME MEASUREMENTS Cutoffs: (1) absolute thickness (yMTT) after CRT < or = 6 mm; (2) relative reduction compared with baseline (ratio yMTT/MTT) < or = 50%. Correlation between EUS measurements and histopathologic tumor regression grade (TRG) and overall survival (OS). RESULTS Sixteen of 56 patients were not included for EUS evaluation (10 severe stenosis, 5 MTT not measured, 1 intolerance to second EUS). Characteristics (n = 40) were as follow: median age, 60 years; squamous cell carcinoma, 42%; and adenocarcinoma (AC), 58%. Initial stage was: 10 T2N1, 3 T3N0, 26 T3N1, 1 T3Nx; 14 of 23 AC Siewert type 1. Wilcoxon rank sum test showed significant correlation of TRG1 with yMTT < or = 6 mm (P = .008) and yMTT/MTT < or = 50% (P = .003). The effect of yMTT on TRG1 was significant (P = .0193; odds ratio, 0.687 [95% CI, 0.502-0.941]). The predefined cutoff of < or = 6 mm for yMTT was predictive for TRG1 (P = .0037; Fisher exact test). After a median follow-up of 28.6 months, there was a clear trend for benefit in OS with yMTT < or = 6 mm and yMTT/MTT < or = 50%. LIMITATIONS Small sample size. CONCLUSION In a multicenter setting, MTT measured by EUS after CRT was highly predictive for response and showed a clear trend for predicting survival.

Protein expression of cancer testis antigens predicts tumor recurrence and treatment response to imatinib in gastrointestinal stromal tumors

Cancer testis antigens (CTAs) have been identified in various tumors as immunological tumor targets. In gastrointestinal stromal tumor (GIST), the prediction of malignant potential remains difficult but is crucial in the era of adjuvant imatinib treatment. Here, we analyzed the impact of CTAs on tumor recurrence and its role on the treatment response to imatinib. The expression of the most frequent CTAs MAGE‐A1, MAGE‐A3, MAGE‐A4, MAGE‐C1 and NY‐ESO‐1 was analyzed by immunohistochemistry. The duration between the initial operation and the tumor relapse was defined as recurrence free survival (RFS). All recurrent cases were treated with imatinib. The tumor response to imatinib was graded according to the modified CT response evaluation criteria. Patients with a CTA positive GIST (n = 23, 27%) had a significantly shorter RFS (p = 0.001) compared to negative cases (n = 63, 73%). The median RFS was 25 months in CTA positive patients and was not reached during the study period in CTA negative patients. According to the established staging criteria CTA positive tumors were predominantly high‐risk tumors (p = 0.001). The expression of MAGE‐A3 (p = 0.018) and NY‐ESO‐1 (p = 0.001) were associated with tumor progression under imatinib treatment. A tendency for worse tumor response to imatinib was observed in CTA positive tumors (p = 0.056). Our study confirms the expression of CTAs in GIST and their role as prognostic markers. It also draws attention to the potential impact of CTAs on the tumor response to imatinib.

Prognostic influence of immunohistochemically detected lymph node micrometastasis and histological subtype in pN0 oesophageal cancer

INTRODUCTION Differences in frequency and clinical impact of lymph node micrometastasis between histological subtypes of oesophageal cancer have not been determined. METHODS 1204 lymph nodes from 32 squamous cell carcinomas and 54 adenocarcinomas with complete resection and pN0 status were re-evaluated using a serial sectioning protocol including immunohistochemistry. Intra-nodal tumour cells were classified as micrometastases (0.2-2 mm) or isolated tumour cells (<0.2 mm). RESULTS There was no significant difference in the frequency of micrometastases between adenocarcinoma and squamous cell carcinoma (11.3% vs. 3.1%, p=n.s.). In the squamous cell carcinoma group, Kaplan-Meier curves showed a significantly prolonged 5-year survival (p=0.02) and disease free interval (p<0.01) for immunohistochemically node negative versus node positive patients. In patients with adenocarcinoma, no such difference (p=n.s. and p=n.s., respectively) was seen. In patients who did not undergo pre-treatment, those with adenocarcinoma had a significant 5-year survival (65% vs. 53%; p=0.03) and disease free interval (83% vs. 58%; p<0.05) advantage over those with squamous cell carcinoma. After pre-treatment, no difference between the histological subtypes was detected. Regression analysis did not reveal any factors that significantly affected overall survival in node negative patients. However, four factors did significantly influence disease free interval: pre-treatment (HR 3.3 [95% CI 1.2-9.1], p=0.02); micrometastasis (HR 5.3 [95% CI 1.4-19.7], p=0.01); UICC stage II vs. 0/I (HR 2.2 [95% CI 1.1-4.4], p=0.03); and adenocarcinoma (HR 0.3 [95% CI 0.1-0.9], p=0.03). CONCLUSION The difference in frequency and clinical impact of immunohistochemically detected micrometastasis may indicate that adenocarcinoma and squamous cell carcinoma should not be treated as one entity.

Use of severity classification systems in the surgical decision-making process in emergency laparotomy for perforated diverticulitis

PurposeHartman’s procedure (HP) or primary anastomosis (PA) are the two surgical techniques used in patients undergoing emergency colectomy for perforated diverticulitis. There are no objective criteria to guide the surgeon’s choice of procedure. This study assesses whether classification and scoring systems can be used in the decision-making process.MethodsOne hundred eleven patients undergoing emergency laparotomy for perforated diverticulitis were analyzed. Logistic regression and interaction models were used to determine the predictive value in the two settings.ResultsSixty five patients underwent HP and 46 patients underwent PA. Patients with HP had significantly higher scores, median age, and were more often on immunosuppressive medication. Mortality and surgical morbidity did not differ between the groups. The clinical anastomotic leak rate was 28.3% in the PA group. In the univariate logistic regression for in-hospital death, all scores showed a significant influence. The multivariate logistic regression analysis showed that only Charlson comorbidity index (CCI) and American Society of Anesthesiologists score had a significant influence on mortality. Each score was analyzed for its predictive value regarding mortality and morbidity with respect to type of operative procedure. Only CCI revealed a trend towards statistical significance. The risk of death increases with increasing CCI when PA is performed compared to HP.ConclusionNone of the tested scores can be used to help the surgeon decide whether a PA or HP is appropriate in a specific patient. Comorbidity, represented as CCI in this study, might be more important than the locoregional situation.

Prospective surgico-pathologic registration study of colorectal cancer (Swiss Group for Clinical Cancer Research SAKK protocol 40/00): Current practices and short-term outcome.

e14053 Background: The short term aim of this study was to estimate the radicality of colorectal cancer resections and to assess the oncosurgical quality of the colorectal specimens. Methods: One G...