No abstract

The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P ¼ 0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2. Modern Pathology (2015) 28, 428-436; doi:10.1038/modpathol.2014 published online 26 September 2014 The molecular mechanisms controlling the maturation and secretion of WNT proteins in the cells responsible for their production are attracting considerable attention. Wntless (WLS) (also known as GPR177 and Evi) was recently discovered as a key modulator of WNT protein secretion. [1][2][3] This multipass transmembrane protein localizes to compartments of the secretory pathway including the Golgi apparatus, endosomes, and plasma membrane. WLS acts as a WNT cargo receptor, shuttling palmitoylated Wnts from the endoplasmic reticulum to the plasma membrane, and it is required for exocytosis of WNT proteins from the WNT-producing cells. 4 In contrast to most other components of the WNT signaling pathway, only a single WLS gene exists in vertebrate genomes. WLS appears to be required for the secretion of all WNT proteins in both the canonical and noncanonical WNT pathways. 5 Augustin et al 6 recently demonstrated that WLS is highly overexpressed in malignant astrocytomas, indicating that the aberrant release of canonical and noncanonical WNT is a potential driver of glioma tumorigenesis required for proliferation, survival, and migration of glioma cells. Their work raises the question of whether WLS has a similar role in other cancers known to have aberrant activation of WNT signaling, including ovarian, gastric, and breast cancers. [7][8][9][10][11][12][13][14][15]

No abstract

These results confirm the continuing value of the necropsy in the assessment of perioperative deaths.

SUMMARY The need for specialised forms of clinical audit was highlighted by the report of the Confidential Enquiry into Perioperative Deaths (CEPOD). Necropsy rates in a Northern Ireland teaching hospital were studied with particular reference to perioperative deaths. To provide an overall context for these observations, the pattern of the necropsy services in Northern Ireland as a whole was also determined. For 600 consecutive deaths in a major teaching hospital, the overall necropsy rate was 180 (30%). In the 74 perioperative deaths in this group (as defined by the CEPOD) the necropsy rate was 26 (35%), compared with 16 out of 72 (22%) for other surgical deaths and 89 out of 386 (23%) for medical cases. More coroners' necropsies were carried out in the perioperative group. These figures are within the range ofthe CEPOD experience. In 1987, in the whole ofNorthern Ireland, there were 8859 hospital deaths, 520 (5-9%) hospital necropsies, and 516 (5-8%) coroners' necropsies, giving an overall necropsy rate of 11-7%. Outside the two major Belfast teaching hospitals, however, there were 6799 hospital deaths, 76-6% of all hospital deaths for Northern Ireland. In this group there were 180 (2-6%) hospital necropsies and 383 (5-6%) coroners' cases, the overall necropsy rate being only 8-2%. These wide variations reflect the fact that the number of pathologists in post in the peripheral areas of the province falls substantially short of levels recommended by the Royal College of Pathologists.Ifclinical audit along CEPOD lines is to be effective nationally, more emphasis should be placed on the value of necropsy and local deficiencies in provision will have to be identified and remedied. It is suggested that this could be achieved by combining audit provisions with budgetary incentives.