Wolfgang Haensch

Immunohistological analysis of E-cadherin, α-, β- and γ-catenin expression in colorectal cancer: implications for cell adhesion and signaling

Intercellular adhesion mediated by the E-cadherin/catenin complex is a prerequisite for epithelial integrity and differentiation. In carcinomas, E-cadherin function is frequently disturbed, and has been suggested to increase invasion and metastasis of tumour cells. beta-catenin has also been implicated in signaling pathways essential for tumour formation. We analysed the E-cadherin/catenin adhesion system of colorectal tumours at different clinical stages. In primary carcinomas (n = 91), there was a frequent reduction in E-cadherin (44%) and alpha-catenin expression (36%). In contrast, beta-catenin and gamma-catenin expression were seldom reduced (4% and 15%, respectively). Similar expression patterns were observed in liver metastases from unrelated colorectal tumours (n = 27). There was a significant relationship between loss of E-cadherin and alpha-catenin expression and poorly differentiated (G3-4) tumours. Our results suggest that reduction of E-cadherin/alpha-catenin expression is a frequent event in primary and metastatic colorectal carcinomas. Furthermore, beta-catenin expression remains normal in colorectal cancer, suggesting the essential role of beta-catenin in signaling pathways.

Expression of Thomsen-Friedenreich-related antigens in primary and metastatic colorectal carcinomas : a reevaluation

Background. Expression of the pancarcinoma Thomsen‐Friedenreich (TF) carbohydrate antigen or, more correctly, hapten, in colorectal carcinomas is not generally agreed on. Furthermore, its suggested role in liver metastasis so far has not been substantiated by direct immunohistochemical evidence.

Transesophageal biopsy of mediastinal and pulmonary tumors by means of endoscopic ultrasound guidance

OBJECTIVE The aim of this study was to investigate the value of endoscopic ultrasound-guided biopsy for the diagnosis of thoracic lesions. METHODS Transesophageal ultrasound-guided biopsy was performed in 29 patients with mediastinal (n = 25) or pulmonary tumors (n = 4). A flexible echoendoscope with a 7.5 MHz curved array transducer (Pentax FG 32 UA, Hamburg, Germany) and a biopsy device with a fine needle (diameter 0.8 mm) were used for all examinations. Three patients were excluded from the analysis of the data because a definite diagnosis based on surgery or follow-up was not available. RESULTS Real-time visualization of the biopsy procedure with endoscopic ultrasound enabled accurate tissue sampling even of small mediastinal lesions with a diameter of less than 1 cm. Diagnostic material was obtained in 23 of the 26 patients (88%). In 3 cases (12%) non-representative biopsy material was found in the specimen. The sensitivity and specificity of transesophageal biopsy in the diagnosis of malignancy were 89% and 83%, respectively. Histologic analysis of the biopsy specimens established malignancy in 17 of 23 patients, whereas benign lesions were diagnosed in 6 patients. Endoscopic ultrasound-guided biopsy confirmed the diagnosis suggested by conventional diagnostic methods in 15 of 23 patients (65%), whereas an unsuspected diagnosis was disclosed in 8 patients (35%). The results of the biopsy had considerable impact on the therapeutic strategy. None of the patients had complications related to the procedure. CONCLUSIONS Endoscopic ultrasound-guided biopsy provides a new minimally invasive approach to the biopsy of lesions in the posterior mediastinum and may complement surgical staging procedures.

Transendoscopic ultrasound of esophageal and gastric cancer using miniaturized ultrasound catheter probes

BACKGROUND The aim of this study was to investigate the value of miniaturized ultrasound catheter probes (miniprobes) for preoperative staging of esophageal and gastric cancer. METHODS Fifty-one patients with esophageal (n = 21) and gastric cancer (n = 30) underwent endoscopic ultrasound (EUS). All examinations were carried out using mechanical miniprobes (diameter 6F, 12.5 MHz) that were introduced through the instrument channel of the endoscope. RESULTS EUS with miniprobes was successfully performed in all patients, although stenotic tumors, which could not be traversed with the endoscope, were found in 6 of 21 patients (29%) with esophageal cancer. Miniprobe scanning provided high-resolution images of the gastrointestinal tract. The overall accuracy in the assessment of tumor infiltration depth for esophageal and gastric cancer was 90% and 82%, respectively. However, the value of miniprobe scanning in the assessment of advanced tumors was limited by the imaging depth of the probe (approximately 3 cm). Lymph node involvement was accurately diagnosed in 78% of the patients with esophageal cancer (sensitivity 75%, specificity 80%) and in 80% of the patients with gastric cancer (sensitivity 73%, specificity 89%). CONCLUSIONS EUS with miniprobes can be performed as single-step procedure during diagnostic endoscopy. The 12.5 MHz transducer provides high-resolution imaging and enables accurate staging of tumors with limited infiltration depth.

Tumor oxygenation correlates with molecular growth determinants in breast cancer

Hypoxic tumor cells may represent a fraction of cells that are not susceptible to radiation or chemotherapy. Intratumoral oxygen partial pressure (pO2) is the result of oxygen delivery and consumption. Cell proliferation is one factor to effect oxygen consumption and we therefore studied the correlation between tumor pO2 and histological parameters. Patients and methods: In 36 women and one man (age range 29–80 years) with suspected breast cancer. Before tumor resection, intralesional pO2 was determined with a polarographic needle electrode. Under ultrasound control, 200 tumor measurements were obtained; Hb levels, Hk, arterial blood gas parameters, and tissue temperature were determined. The median of pO2 values and the percentage of hypoxic areas (pO2 < 10 mmHg) were calculated and correlated with the histological type, grading, ER, PR, and the expression of Ki-67, p53, EGFR, pS2, and c-erb-B2. Results: The overall median pO2 was 44 mmHg, and 1024 measurements (13.8%) represented hypoxic areas. Ductal and lobular invasive cancers showed median pO2 of 41 mmHg. The mean pO2 of G1 tumors was 59 mmHg and the hypoxic fraction 8%, in contrast to G2 tumors with 43 mmHg and 17%, and G3 tumors with 36 mmHg and 20.4% (p < 0.01). We observed a correlation with tumor size and an increased rate of hypoxic areas in T3–4 lesions (p < 0.02). Also tumors with negative nodes or positive ER had significantly higher pO2 values, as did tumors with an overexpression of c-erb-B2, p53, and cathepsin D. Conclusion: Oxygenation of human breast cancers can safely be measured in patients prior to surgical therapy. pO2 values correlate both with prognostic markers examined histologically and with molecular growth factors. As the efficacy of preoperative or adjuvant treatment in individuals may depend on oxygen partial pressure, efforts to manipulate tumor pO2 for therapeutic purpose could be promising.

Clinical Relevance of Sialyltransferases ST6GAL-I and ST3GAL-III in Gastric Cancer

Aberrant glycosylation of membrane components due to specific alterations of glycosyltransferase activity is a common feature of carcinoma cells and is usually associated with invasion and metastasis. In a prospective study, the enzyme activity of the sialyltransferases ST6GAL-I and ST3GAL-III was studied in gastric cancer and normal mucosa in 55 patients by a radiometric assay. Cellular localization of sialyltransferase ST6GAL-I mRNA expression was studied by in situ hybridization. Sialyltransferase ST6GAL-I mRNA expression was mainly localized to epithelial cells. ST6GAL-I enzyme activity was enhanced within the tumor tissue. Significant correlations were found between the presence of signet ring cells and enhanced ST6GAL-I activity in the tumor tissue (p = 0.047) or in the mucosa (p = 0.024), and between signet ring cells and ST3GAL-III activity in the mucosa (p < 0.001). Multivariate Cox analysis demonstrated that only lymph node metastases (p = 0.044) had a significant influence on tumor-related survival. ST3GAL-III and ST6GAL-I activity showed no independent prognostic relevance in multivariate analysis, but high levels of ST3GAL-III and ST6GAL-I in the tumor tissue correlated with secondary local tumor recurrence (p = 0.005; p = 0.012). Interestingly, also the nonmalignant and uninvolved mucosa of tumor patients was altered on the molecular level and in some cases showed enhanced sialyltransferase levels indicative of the alteration of glycosylation very early during tumorigenesis.

Deletion mapping and linkage analysis provide strong indication for the involvement of the human chromosome region 8p12-p22 in breast carcinogenesis.

We have identified a high frequency of loss of heterozygosity (LOH) on the human chromosome region 8p12-p22 in a panel of microdissected familial (86% LOH) and sporadic (74% LOH) breast tumours. The two most frequently deleted regions were defined around marker D8S133 and in a broader centromeric region bounded by markers D8S137 and D8S339. We cannot unequivocally characterize the 8p12-p22 loss as an early or a late event in breast carcinogenesis. In parallel, we have performed linkage analysis in four German breast cancer families. A location score greater than 13.67 corresponding to a LOD score of 2.97 at the marker D8S137 has been obtained. Our results considerably strengthen the evidence for a breast cancer susceptibility gene(s) located on the short arm of the chromosome region at 8p12-p22.

Evaluation and biopsy of recurrent rectal cancer using three-dimensional endosonography.

PURPOSE: The value of endorectal ultrasonography for postoperative follow-up of rectal cancer is limited by the inability to distinguish recurrent malignancy from benign lesions,e.g., fibrotic tissue. This study was conducted to investigate the role of three-dimensional (3D) endosonography for evaluation and biopsy of recurrent rectal cancer. METHODS: Endorectal ultrasonography was performed in routine follow-up program after resection of rectal cancer. 3D volume scans were recorded using a bifocal multiplane 3D transducer (7.5/10 MHz) with a 100‡ longitudinal and a 360‡ transversal scan angle. For transrectal ultrasound-guided biopsy of pararectal lesions, a specially designed targeting device was attached to the endoprobe. RESULTS: Overall pararectal lesions were detected in 28 of 163 patients (17 percent) who were undergoing endorectal ultrasonography for follow-up after resection of rectal cancer. 3D image analysis facilitated assessment of suspicious pararectal lesions by contemporary display of three perpendicular scan planes or volume reconstructions of the scanned area. Ultrasound-guided biopsy was performed in all 28 patients with pararectal lesions identified by endorectal ultrasonography. Biopsy revealed recurrent disease or lymph node metastases in seven and two patients, respectively. Benign lesions explained the endosonographic findings in 17 patients. All patients with benign histology still have no evidence of recurrent disease after a median follow-up of seven months. Nonrepresentative material was obtained in only 2 of 28 patients (accuracy, 93 percent). Histology changed the endosonographic diagnosis in 28 percent of cases. CONCLUSIONS: 3D endosonography with ultrasound-guided biopsy improves the diagnosis of extramural recurrence after curative resection of rectal cancer. 3D image display allows precise control of the position of the biopsy needle within the target.

Expression of the mdr1 gene in bone and soft tissue sarcomas of adult patients

The expression of the mdr1 gene was evaluated at the RNA level by northern and slot blot analysis, and at the protein level by immunohistochemistry, in a total of 29 bone and 32 soft tissue sarcomas. All patients, mainly adults, had not received previous chemotherapy. Of the tumours investigated, 69% were mdr1-positive. An intermediate mdr1 expression was observed most frequently, with the exception of osteosarcomas (high) and malignant fibrous histiocytomas (low). Detection of P-glycoprotein in selected tumours revealed consistent results. However, no conclusion can be drawn as yet regarding correlation of mdr1 expression and drug resistance in patients.

Detailed deletion mapping in sporadic breast cancer at chromosomal region 17p13 distal to the TP53 gene: association with clinicopathological parameters

Chromosome 17p is among the most frequently deleted regions in a variety of human malignancies including breast cancer. This study has further refined the localization of a putative tumour suppressor gene (TSG) at 17p13 distal to the TP53 gene in breast carcinomas. It was found that 73% (37 of 51) of the breast tumours exhibited loss of heterozygosity (LOH) at one or more loci at 17p13. The allelic loss patterns of these tumours suggest the presence of at least seven commonly deleted regions on 17p13. The three most frequently deleted regions were mapped at chromosomal location 17p13.3–17p13.2 between the markers D17S831 and D17S1845 (56% LOH), at 17p13.1 between D17S1810 and D17S1832 (53% LOH), and at 17p13.1 between D17S938 and TP53 (55% LOH). A significant correlation was found between loss at 17p13 and tumour grade, size, proliferative activity, and oestrogen receptor (ER) status. Losses at 17p13 were seen more frequently in large and poorly differentiated tumours with high proliferative activity. These data support and extend previous reports on the presence of a putative TSG(s) at chromosomal region 17p13 distal to the TP53 gene and show that different subsets of LOH are associated with more aggressive tumour behaviour. Copyright