Citations

Abstract Reflux-induced injury promotes esophageal adenocarcinoma, one of the most rapidly increasing, highly lethal cancers in Western countries. Here, we investigate the efficacy of a combinatorial chemoprevention strategy for esophageal adenocarcinoma and characterize the underlying molecular mechanisms. Specifically, our approach involves the use of ursodeoxycholic acid (Urso) due to its ability to decrease injury-inducing bile salts in combination with Aspirin to mitigate the consequences of injury. We find that Urso-Aspirin combination reduces the risk of adenocarcinoma in vivo in animals with reflux, decreases the proliferation of esophageal adenocarcinoma cells, and downregulates a key cell cycle regulator, CDK2. Mechanistically, using cell growth, luciferase reporter, expression, and chromatin immunoprecipitation assays, we identify GLI1, a Hedgehog-regulated transcription factor, as a novel target of Urso-Aspirin combination. We show that GLI1 is upregulated during esophageal carcinogenesis, and GLI1 can bind to the CDK2 promoter and activate its expression. Although the Urso-Aspirin combination downregulates GLI1, the GLI1 overexpression not only abrogates the effect of this combination on proliferation but it also restores CDK-2 expression. These findings support that the chemopreventive effect of the Urso-Aspirin combination occurs, at least in part, through a novel GLI1-CDK2–dependent mechanism. To further understand the regulation of CDK2 by GLI1, both pharmacologic and RNAi-mediated approaches show that GLI1 is a transcriptional activator of CDK2, and this regulation occurs independent of Smoothened, the central transducer of the Hedgehog canonical pathway. Collectively, these results identify a novel GLI1-to-CDK2 pathway in esophageal carcinogenesis, which is a bona fide target for effective combinatorial chemoprevention with Urso and Aspirin. Cancer Res; 70(17); 6787–96. ©2010 AACR.

Mechanical ventricular assistance has become a reliable tool for the support of children and infants with heart failure. The devices have shown efficacy both as a bridge to transplantation and as a bridge to recovery. The potential complications that may occur with long-term support have not been fully described. This article reports the occurrence of a large pseudoaneurysm associated with the ascending aorta following explantation of the EXCOR Pediatric ventricular assist device. A management strategy for this potentially lethal complication is described.

Irreparable mitral pathology may lead to early mitral valve replacement (MVR) in children. Often, a small mechanical prosthesis (<23 mm) is required, raising concerns about annular growth in patients who may eventually require subsequent mitral valve re-replacement (MVRR). The aim of this study was to evaluate interval mitral annular growth in this cohort. Between January 1972 and December 2006, 164 children underwent MVR with a mechanical prosthesis; 110 of these children (median age, 4 years; range, 7 days to 14 years) received a small mechanical prosthesis (<23 mm). The most common diagnoses were congenital mitral stenosis (10%), regurgitation (46%), and left atrioventricular valve dysfunction after previous atrioventricular septal defect repair (44%). The cohort was analyzed for age, body surface area (BSA), prosthesis size, and Z score at the time of MVR and MVRR. At the time of MVR, 78 patients had a BSA of 0.77 ± 0.06 m2, had an annular size of 24 ± 0.62 mm ( Z score, 2.91 ± 0.23), and ultimately did not require MVRR. Another cohort, who eventually did require MVRR (n = 24), had an initial BSA at the time of MVR of 0.62 ± 0.05 m2 ( P = NS vs MVR only) and an annular size of 20 ± 0.49 mm ( Z score, 1.85 ± 0.22) ( P = .008 vs MVR only). In the interval between MVR and MVRR (7.8 ± 1.1 years), BSA increased to 1.12 ± 0.07 m2, and annulus size increased to 24 ± 0.47 mm ( Z score, 1.80 ± 0.28). These data suggest growth of the mitral annulus following MVR with a small mechanical prosthesis, as evidenced by an unchanged Z score in the setting of normal interval increase in BSA. Additionally, there was a statistically significant difference in initial Z scores between the cohorts requiring MVRR and those who have not needed re-replacement, suggesting that the feasibility of placement of a slightly larger prosthesis may be associated with a decreased need for MVRR.

Purpose We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. Methods We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m 2 . Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. Results Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). Conclusion Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin.

The current study sought to provide practical information for the clinical use of child and parent reports of child anxiety symptoms by investigating agreement between parent, child, and clinician as well as the predictive value of this information. Examining 88 anxious children and their parents, the study compared agreement by correlating parent and child responses on the Spence Children’s Anxiety Scale (SCAS); comparing parent and child responses to clinician data operationalized through continuous and dichotomous variables from the Anxiety Disorder Interview Schedule for Children; and examining the relative clinical utility of parent and child reports on the SCAS in terms of positive and negative predictive value. Results indicated that parent and child agreement on the SCAS was moderate to high for most anxiety disorder symptoms and that both were generally consistent with clinician impressions. Moreover, both child and parent provided unique information to the diagnostic process.

AbstractPurposeNumerous surgical techniques have been described for the treatment of peroneal nerve palsy after knee dislocation with less than optimal outcomes. The purpose of this article is to present a review of the literature including modern surgical treatment options for peroneal nerve palsy after knee dislocation.MethodReview of the current body of literature relevant to the topic was undertaken and summarized accordingly. Mechanism of injury, pathology and prognosis as well as current and novel treatment options are presented.ResultsNeurolysis and nerve grafting results are dependant on nerve graft length, with documented recovery rates of only 44% for nerve grafts longer than 6 cm. Posterior tibial tendon transfer procedures have had reasonable success in allowing patients to return to ambulation without assistive devices; however, dorsiflexion strength on the affected side has been reported at only 30% that of the normal contralateral side, and return to activities more strenuous than walking has not been reported. Future concepts including partial nerve transfer of a motor branch of the tibial nerve to the peroneal nerve have been described, but no outcome data is currently available.ConclusionPeroneal nerve palsy after knee dislocation leads to significant functional impairment. Prior treatment strategies utilized for restoration of dorsiflexion and peroneal nerve function have yielded overall poor results. Newer surgical techniques are being developed and clinical trials are under way to evaluate their effectiveness.