For the p53 Special IssueIn this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH. Hum Mutat 21:258-270,

Until recently, two major forms of colorectal epithelial polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were perceived to represent the precursor to colorectal cancer, whereas hyperplastic polyps were viewed as innocuous lesions with no potential for progression to malignancy. We now recognize, however, that the lesions formerly classified as hyperplastic actually represent a heterogeneous group of polyps, some of which have a significant risk for neoplastic transformation. These serrated polyps include not only hyperplastic polyps but also traditional serrated adenomas and sessile serrated adenomas. These polyps demonstrate characteristic molecular alterations not commonly seen in colorectal adenomas, and they probably progress to colorectal cancer by means of a new pathway: the serrated neoplasia pathway. The morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development are discussed herein.

To our knowledge, this is the largest American single-center experience demonstrating that CBE-EMR with close endoscopic surveillance is an effective treatment modality for BE with HGD/IMC. Although the rate of stenosis development is significant, it is easily treated by endoscopic dilation. Patients considering endoscopic ablation should be counseled appropriately. The role of CBE-EMR in patients with lymphatic invasion or superficial submucosal invasion remains to be defined.

In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.

CBE-EMR is a safe and highly effective long-term treatment that should be offered to all patients with Barrett's esophagus with HGD and IMC.

Prostate-specific membrane antigen is a type II transmembrane glycoprotein, expressed in benign and neoplastic prostatic tissue as well as endothelial cells of neovasculature from a variety of tumors. The expression of prostate-specific membrane antigen in nonneoplastic neovasculature has not been well studied. Therefore, we studied nonneoplastic reparative and regenerative human tissues, as well as preneoplastic tissue, to determine the presence of prostate-specific membrane antigen-expressing neovasculature. Formalinfixed paraffin-embedded tissue from keloids, granulation tissue from heart valves and pleura, proliferative and secretory endometrium, and Barrett's mucosa with and without dysplasia were stained for the expression of prostate-specific membrane antigen (3E6). Vessels of proliferative, mid-secretory, and late secretory endometrium were consistently strongly positive for prostate-specific membrane antigen expression in all ten cases of each type (100%). Vessels associated with granulation tissue from pleural peels and heart valves were positive in 10 of 12 cases (83%) and 7 of 10 cases (70%), respectively. Keloids had prostate-specific membrane antigen-expressing endothelial cells in 6 of 15 cases (40%). Prostate-specific membrane antigen was not expressed by vessels associated with Barrett's mucosa with low-grade dysplasia (12 foci), high-grade dysplasia (24 foci), or no dysplasia (18 foci). A variety of nonneoplastic neovasculature expresses prostatespecific membrane antigen, including vessels in proliferative endometrium, granulation tissue, and some scars. This is the first study showing that prostate-specific membrane antigen is expressed in neovasculature from physiologic regenerative and reparative conditions. The folate hydrolase activity of prostate-specific membrane antigen may facilitate vasculogenesis and angiogenesis by increasing local availability of folic acid. These findings will enhance our overall understanding of blood vessel development and will enable us to better understand the effects of anti-prostate-specific membrane antigen therapies, which are already being explored in clinical trials.

Telepathology (TP) is the practice of remote diagnostic consultation of electronically transmitted, static, digitalized images. The diagnostic efficacy of TP-based consultation services has not been widely tested. Dysplasia that arises in association with chronic ulcerative colitis (CUC) is, at present, the most important marker of an increased risk of malignancy in patients with this disease. Unfortunately, dysplasia is difficult to diagnose histologically and, as a result, suffers from a significant degree of intra- and interobserver variability. Furthermore, it is often necessary to obtain expert consultation of potential CUC-associated dysplasia cases before treatment. Therefore, the aim of this study was to evaluate the utility and interobserver variability of diagnosing dysplasia in CUC with the use of TP. Static, electronically transmitted, digitalized images of 38 CUC cases with areas considered negative, indefinite, or positive for dysplasia (low or high grade) were evaluated independently by four gastrointestinal pathologists. All cases were then graded by each of the pathologists by light-microscopic examination of the hematoxylin and eosin-stained glass slides. The degree of interobserver variability was determined by kappa statistics. Overall, there was a fair degree of agreement (kappa = 0.4) among the four reviewing pathologists after analysis of the digitalized images. The poorest level of agreement was in the indefinite and low-grade dysplasia categories. Grouping together several diagnostic categories (for instance, indefinite and low-grade dysplasia, or low-grade dysplasia and high-grade dysplasia) had no effect on the overall level of agreement. The degree of variability in interpretation of glass slides was slightly better (kappa = 0.43) but still remained fair. After reviewing all cases by glass slide analysis, the diagnosis was changed in 38% of the slides; in the majority of these, the grade of dysplasia was increased. Use of TP for consultation in CUC-associated dysplasia has a moderate level of interobserver agreement. Because of a variety of technical reasons, diagnoses rendered by evaluation of digitalized images tended to be of a lower grade than that observed after a review of the glass slides.

Background-The management of low-grade (LGD) and indefinite dysplasia (IND) in patients with ulcerative colitis (UC) remains controversial, as outcomes after a diagnosis of LGD or IND in previous studies vary widely.