HER-2 status in primary oesophageal cancer, lymph nodes and distant metastases.

BACKGROUND: Some 10-15 per cent of patients with oesophageal cancer overexpress human epidermal growth factor receptor (HER) 2 at the primary tumour site, leading to the hope that specific targeted systemic therapy might favourably influence clinical and subclinical disease at locoregional and distant sites. This approach is based on primary tumour characteristics, without knowledge of expression patterns at metastatic sites. In oesophageal cancer, concordance between HER-2 status at the primary tumour and other sites is unknown. METHODS: The HER-2 status of primary tumours and corresponding metastatic sites (lymph node and distant) and local recurrence were evaluated in a series of patients with oesophageal cancer, using immunohistochemistry and dual colorimetric in situ hybridization. RESULTS: There were 97 adenocarcinomas (ACs) and 79 squamous cell carcinomas (SCCs). Some 14 per cent of primary ACs and 1 per cent of primary SCCs were staged as HER-2-positive. The HER-2 status was identical in the primary tumour and lymph node metastases in 95 per cent of ACs and 99 per cent of SCCs respectively (P = 0·375, sign test). Nineteen of 22 distant metastases from AC and all from SCC had identical HER-2 status to the primary tumour. In two of 22 patients with AC the primary tumour was classed as negative but distant metastases were HER-2-positive. CONCLUSION: With over 85 per cent concordance in HER-2 status between primary tumours and distant metastases in oesophageal cancer, routine HER-2 testing of metastases to confirm HER-2 positivity is not warranted. Assessment of HER-2 status at metastatic sites may be worthwhile in some patients with easily accessible metastases and negative HER-2 status at the primary tumour, or if adequate material cannot be obtained from the primary site.

Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa.

Saccharomyces boulardii is a nonpathogenic yeast used in the treatment of Clostridium difficile diarrhea and colitis. We have reported that S. boulardii inhibits C. difficile toxin A enteritis in rats by releasing a 54-kDa protease which digests the toxin A molecule and its brush border membrane (BBM) receptor (I. Castagliuolo, J. T. LaMont, S. T. Nikulasson, and C. Pothoulakis, Infect. Immun. 64:5225-5232, 1996). The aim of this study was to further evaluate the role of S. boulardii protease in preventing C. difficile toxin A enteritis in rat ileum and determine whether it protects human colonic mucosa from C. difficile toxins. A polyclonal rabbit antiserum raised against purified S. boulardii serine protease inhibited by 73% the proteolytic activity present in S. boulardii conditioned medium in vitro. The anti-protease immunoglobulin G (IgG) prevented the action of S. boulardii on toxin A-induced intestinal secretion and mucosal permeability to [3H]mannitol in rat ileal loops, while control rabbit IgG had no effect. The anti-protease IgG also prevented the effects of S. boulardii protease on digestion of toxins A and B and on binding of [3H]toxin A and [3H]toxin B to purified human colonic BBM. Purified S. boulardii protease reversed toxin A- and toxin B-induced inhibition of protein synthesis in human colonic (HT-29) cells. Furthermore, toxin A- and B-induced drops in transepithelial resistance in human colonic mucosa mounted in Ussing chambers were reversed by 60 and 68%, respectively, by preexposing the toxins to S. boulardii protease. We conclude that the protective effects of S. boulardii on C. difficile-induced inflammatory diarrhea in humans are due, at least in part, to proteolytic digestion of toxin A and B molecules by a secreted protease.