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.

SUMMARYBackground: Colorectal cancer in primary sclerosing cholangitis patients with ulcerative colitis is mostly right-sided where concentrations of carcinogenic secondary bile acids are highest. Aim: To investigate whether ursodeoxycholic acid could be chemopreventive for colorectal cancer. Methods: A historical cohort study was performed on primary sclerosing cholangitis patients with ulcerative colitis where the 28 patients (cases) who were treated with ursodeoxycholic acid for at least 6 months (mean 3.4 ± 2.7 years) were compared with the 92 patients (controls) who were not treated with ursodeoxycholic

Chronic viral hepatitis frequently goes undetected until cirrhosis develops. Although the effect of interferon on the natural history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in asymptomatic persons is unknown, treatment may modify the course of the infection, producing cures in some. In September 1992, screening for HBV and HCV was offered in 40 centers throughout the United States. Demographic features, potential risk factors, and symptoms were studied. Blood samples were obtained for the determination of serum alanine aminotransferase levels and for markers of HBV and HCV infection. Thirteen thousand nine hundred ninety seven subjects were screened. The prevalence of infection with HBV or HCV was 24.8% (HBV 17.8%; HCV 7.0%; and both 2.8%). Hepatitis B and C disease was present in 0.7% and 4.4% of the population, respectively. Risk factors for HBV and HCV infection were similar in: blood transfusions, hemodialysis, IV drug use, and sex with an IV drug user. For HBV infection, sex with multiple partners, increasing age, and birth in South East Asia or Africa were additional risk factors. The cost to find a case of HCV infection is less than the costs for finding many other treatable diseases. Screening for HBV, though more costly, is reasonably efficient, and simultaneous screening for HBV and HCV provides greater efficiency. It is practical to consider screening for HBV and HCV in the United States, particularly if any risk factor is present. Improved treatment strategies will make screening even more cost effective.

Proteasome inhibition following DNA damage results in the synergistic induction of apoptosis via a nuclear factor-KBindependent mechanism. In this study, we identify the role of p53 in mediating apoptosis by the sequence-specific treatment involving the DNA-damaging, topoisomerase I -targeting drug SN-38 followed by the proteasome inhibitor PS-341 (SN-38!PS-341). The p53-dependent sensitization of DNA damage -induced apoptosis by PS-341 is accompanied by persistent inhibition of proteasome activity and increased cytosolic accumulation of p53, including higher molecular weight forms likely representing ubiquitinated species. In contrast, pretreatment with PS-341 followed by treatment with SN-38 (PS-341!SN-38), which leads to an antagonistic interaction, results in transient inhibition of proteasome activity and accumulation of significantly lower levels of p53 localized primarily to the nucleus. Whereas cells treated with PS-341!SN-38 undergo G 2 + M cell cycle arrest, cells treated with SN-38!PS-341 exhibit a decreased G 2 + M block with a concomitant increase in the sub-G 1 population. Decreased accumulation of cells in the G 2 + M phase of the cell cycle in SN-38!PS-341 -treated cells compared with PS-341!SN-38 -treated cells correlates with enhanced apoptosis and reduced expression of two p53-modulated proteins, 14-3-3S and survivin, both of which play critical roles in regulating G 2 + M progression and apoptosis. The functional role of 14-3-3S or survivin in regulating the divergent function of p53 in response to SN-38!PS-341 and PS-341!SN-38 treatment in inducing apoptosis versus G 2 + M arrest/DNA repair, respectively, was confirmed by targeted down-regulation of these proteins. These results provide insights into the mechanisms by which inhibition of proteasome activity modulates DNA damage-induced apoptosis via a p53-dependent pathway. [Mol Cancer Ther 2005;4(12):1880 -90]

Results: There were 12,183 low risk, 17,236 intermediate risk, 7,622 high risk, and 605 locally advanced patients. In the low risk group, AS was the only recommended treatment option for 2941 patients; 712 (24%) were treated with AS, the remainder were treated with EBRT (25%), brachytherapy (20%), EBRT+brachytherapy (3%), or radical prostatectomy (18%). In the low risk group, AS was an accepted option for 9,242 patients; 1624 (18%) were treated with AS, the remainder were treated with EBRT (17%), brachytherapy (21%), EBRT+brachytherapy (3%), or radical prostatectomy (35%). In the intermediate risk group, AS was an accepted option for 5,084 patients; 1,281 (25%) were treated with AS; the remainder were treated with EBRT (29%), brachytherapy (9%), EBRT+brachytherapy (6%) or radical prostatectomy (24%). The NCCN guidelines do not recommend AS for the other risk groups. Overall, 46% of all patients could be managed with AS according to the guidelines; 9.6% actually received it. Based on an annual U.S. prostate cancer incidence of 192,000; we estimate that approximately 88,000 patients could initially be treated with AS by following the NCCN guidelines, while 18 thousand were actually treated with it. The remaining 70,000 were treated with radical prostatectomy (25,000), EBRT (19,000), brachytherapy (15,000), EBRT + brachytherapy (3000), and other treatments (6000). Conclusions: Based on NCCN guidelines, active surveillance could be an acceptable treatment option for almost half of all patients diagnosed with prostate cancer, though less than 10% actually received it in 2006. Nationally, up to 70,000 additional patients with prostate cancer could be managed initially with active surveillance rather than radical therapy.