CRSBP‐1 (mammalian LYVE‐1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF‐BB and VEGF‐A) containing CRS motifs (clusters of basic amino‐acid residues). The ligand binding activities are mediated by Link module and acidic‐amino‐acid‐rich (AAAR) domains, respectively. These CRSBP‐1/LYVE‐1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild‐type mice. We hypothesize that CRSBP‐1/LYVE‐1 ligands, particularly CRS‐containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE‐1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE‐1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE‐1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP‐1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF‐BB and VEGF‐A, respectively, specifically bind to CRSBP‐1 but do not interact with either PDGFβR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE‐1 is involved in adaptive immunity in mammals.

ABSTRACTFor several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF‐β, an anti‐inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF‐β signaling (Smad2‐dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF‐β signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7‐dehydrocholesterol (7‐DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF‐β signaling. We use Mv1Lu cells (a model cell system for studying TGF‐β activity) stably expressing the Smad2‐dependent luciferase reporter gene. We demonstrate that 7‐DHC (but not cholesterol or other sterols) effectively suppresses the TGF‐β‐stimulated luciferase activity. We also demonstrate that 7‐DHC suppresses TGF‐β‐stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell‐surface TGF‐β receptors from non‐lipid raft microdomains to lipid rafts/caveolae where TGF‐β receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF‐β binding. We determine this by cell‐surface 125I‐TGF‐β‐cross‐linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl‐β‐cyclodextrin (MβCD), a sterol‐chelating agent, reverses 7‐DHC‐induced suppression of TGF‐β‐stimulated luciferase activity by extrusion of 7‐DHC from resident lipid rafts/caveolae. These results suggest that 7‐DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF‐β signaling and atherogenesis. J. Cell. Biochem. 118: 1387–1400, 2017. © 2016 Wiley Periodicals, Inc.

Barring unusual circumstances, sigmoid colostomy is the optimal technique for management of defecation in spinal cord injury (SCI) patients. We sought to provide evidence that a sigmoid colostomy is not difficult to perform in SCI patients and has better long-term results. The St. Louis Department of Veterans Affairs has a Commission on Accreditation of Rehabilitation Facilities (CARF)–approved SCI Unit. We reviewed the operative notes on all SCI patients who received a colostomy for fecal management by three ASCRS-certified colorectal surgeons at the St. Louis Department of Veterans Affairs from January 1,2007 to November 26, 2012. There were 27 operations for which the recorded indication for surgery suggested that the primary disorder was SCI. Fourteen had traumatic SCI of the thoracic and/or lumbar spine and were evaluable. Of these 14 patients, 12 had laparoscopic sigmoid colostomy and two had open sigmoid colostomy. We encountered one evaluable patient with a remarkably large amount of retroperitoneal bony debris who successfully underwent laparoscopic sigmoid colostomy. In conclusion, sigmoid colostomy is the consensus optimal procedure for fecal management in SCI patients. Laparoscopic procedures are preferred. Care providers should specify sigmoid colostomy when contacting a surgeon.

INTRODUCTION: An aberrant course of the distal ureter can pose a risk of ureteral injury during surgery for inguinal hernia repair and other groin operations. In a recent case series of inguinoscrotal hernation of the ureter, we found that each affected ureter was markedly anterior to the psoas muscle at its mid-point on abdominal CT. We hypothesized that this abnormality in the abdominal course of the ureter would predict the potentially hazardous aberrant course of the distal ureter.PRESENTATION OF CASES: We reviewed all evaluable CT urograms performed at St. Louis University Hospital from June 2012 to July 2013 and measured the ureteral course at several anatomically fixed points.DISCUSSION: 93% (50/54) of ureters deviated by less than 1 cm from the psoas muscle in their midcourse (at the level of the L4 vertebra). Reasons for anterior deviation of the ureter in this study included morbid obesity with prominent retroperitoneal fat, congenital renal abnormality, and post-traumatic renal/retroperitoneal hematoma. We determined that the optimal level on abdominal CT to detect the displaced ureter was the mid-body of the L4 vertebra.CONCLUSION: Anterior deviation of the ureter in its mid-course appears to predict inguinoscrotal herniation of the ureter. This finding is a sensitive predictor and should raise concern for this anomaly in the appropriate clinical setting. It is not entirely specific as morbid obesity and congenital anomalies may result in a similar imaging appearance. We believe that this association has not been reported previously. Awareness of this anomaly can have significant operative implications. (C) 2016 The Authors. Published by Elsevier Ltd. on behalf of IJS Publishing Group Ltd.

Given that ovarian cancer has a generally poor prognosis and tends to recur with low survival rates, surveillance of these cancers after treatment is vital. However surveillance strategies tend to vary among gynecologic oncologists. Objective: This survey was conducted to evaluate if initial International Federation of Gynecology and Obstetrics stage accounts for the variation in surveillance strategies used by gynecologic oncologists after initial curative-intent treatment for ovarian carcinoma. Materials and Methods: We created a survey instrument directed to the Society of Gynecologic Oncology (SGO). The survey was conducted by e-mail and included SGO members and candidate members. The 943 SGO members were asked to report how frequently they recommended 11 surveillance modalities in years 1-5 and 10 after primary treatment. Statistical evaluation included generalized linear models with a Poisson distribution. Results: Two hundred and eighty-three of the survey results were evaluable. For several surveillance modalities (office visit, pelvic examination, complete blood count, serum CA-125 level, and comprehensive metabolic panel), the frequency of recommended use was statistically significantly greater for more advanced stage tumors. Conclusions: The intensity of surveillance recommended by practicing gynecologic oncologists varies significantly based on initial patient stage and perceived prognosis. However, the variability related to initial prognosis is clinically small and cannot account for the overall variability previously reported.

Johnson, Frank E. MD, FACS; Olsen, Stephen P. MD; Armbrecht, Eric S. PhD; Zeitouni, Nathalie C. MD; Rosman, Ilana S. MD; Priddy, Anna M.; Perez, Matthew C. MD; Paquette, Anne D.; Behera, Anit K.; Council, Laurin M. Author Information

BACKGROUND:Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS:Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS:From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION:Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV:NCT02409472.

6547 Background: The mean lifetime cost of surveillance for a woman diagnosed with breast cancer at age 45 is estimated to be > $35,000. Based on trials comparing low and high intensity surveillance, ASCO and NCCN have published recommendations encouraging low intensity strategies. We aimed to determine whether ASCO experts carry out surveillance differently for patients with breast cancer of varying TNM stages. Methods: We created a web-based survey instrument with 4 idealized patient vignettes depicting patients with TNM stages 0 to IIIA. Respondents were asked how often they would recommend 12 specific diagnostic modalities for each vignette during post-treatment years 1-5. The survey was e-mailed to the 3245 ASCO members who had identified breast cancer as their major clinical focus. We used repeated measures ANOVA for analysis. Results: 1,012 (31%) of the 3245 ASCO members surveyed responded. There were 915 (90%) evaluable responses. Office visit was most frequently recommended. Responders also commonly recommended complete blood count (CBC), liver function tests (LFTs), and mammogram. There was statistically significant variation in recommended surveillance intensity for all 12 modalities according to TNM stage. Conclusions: We have demonstrated significant variability in surveillance after curative-intent treatment. Modalities not recommended by ASCO guidelines, such as CBC and LFTs, are frequently recommended by physicians. The frequency of recommended modalities varied depending on the TNM stage of the described patients, but ASCO guidelines do not stratify according to TNM stage. Our results suggest both overuse and underuse of surveillance modalities. Innovative solutions to promote physician and patient education can help physicians follow evidence-based surveillance guidelines and help patients to participate in these decisions. There is a need for new randomized controlled trials to evaluate newer surveillance modalities to guide clinical practice. Frequency of recommended use of office visits: mean ± SD. Year TisN0M0 T2N0M0 T1N1M0 T3N2M0 1 2.8 ± 1.2 3.3 ± 1.3 3.3 ± 1.2 4.1 ± 2.2 2 2.5 ± 1.2 3.0 ± 1.1 3.0 ± 1.1 3.3 ± 1.2 3 2.1 ± 1.3 2.4 ± 1.1 2.5 ± 1.2 2.7 ± 1.3 4 2.0 ± 1.4 2.2 ± 1.1 2.3 ± 1.3 2.5 ± 1.3 5 1.9 ± 1.5 2.1 ± 1.3 2.2 ± 1.3 2.4 ± 1.3

Aims: In the vast majority of instances, closure of abdominal wall defects relies on the tensile strength of transposed native tissue and/or prosthetic material. The purpose of this report is to alert clinicians to a different strategy for closure that we have used successfully on several occasions. Presentation of Case: A 72 year old man had a bulky inguinal nodal metastasis from cutaneous squamous cell carcinoma. He had an extended radical groin dissection including full thickness abdominal wall resection, with primary closure, followed by external beam radiotherapy. After 30 months, he developed an abdominal wall hernia and enterocutaneous fistula at the surgical site. Direct closure and local vascularized flaps were not feasible. Obturation of the defect by omentum was employed, taking advantage of its relative incompressibility rather than its minimal tensile strength. The wound was subsequently covered by a skin graft. The patient survived 10 years with an intact hernia repair and died of unrelated causes. Discussion: The technique has yielded good results. Case Study Johnson et al.; BJMMR, 7(12): 1039-1043, 2015; Article no.BJMMR.2015.42

e16538 Background: In the USA, ovarian cancer is the eighth most common cancer in women; about 21,000 new cases are diagnosed each year. Many women experience recurrence after curative-intent treatment. Post-treatment surveillance is felt to be useful. Consensus-based surveillance guidelines exist, but high-quality evidence is not available. We recently carried out a survey of the Society of Gynecologic Oncologists which documented marked variation in the intensity of surveillance (Gynecol Oncol 120: 205-207, 2011). We sought to determine whether Consolidated Metropolitan Statistical Area (CMSA) could explain the variation in surveillance intensity. Methods: The 943 SGO members were surveyed to determine their surveillance practices. Our survey offered 4 idealized clinical vignettes and a menu of 11 testing modalities. Responses were stratified by CMSA. Repeated-measures ANOVA was used to generate mean, SD, median, and range. Results: 323 of those surveyed responded; 283 were evaluable. There was statistically significant variation (p<0.05) in only one of the most frequently utilized modalities: CBC. Physicians in the TX CMSA recommended 0.3±0.5 CBCs in year 1; those in the NY-NJ-CT-PA CMSA recommended 1.2±1.5 CBCs in year 1. Conclusions: There is very little variation in the utilization of surveillance modalities among CMSAs. Number of surveillance modalities per year (mean ± SD). Location Number of MDs Office visit Pelvic exam Pap smear CBC Metabolic panel CA-125 level Chest x-ray Abdomen-pelvic CT TX CMSA 10 3.8±0.4 3.9±0.3 1.0±0.0 0.3±0.5 0.2±0.4 3.9±0.3 0.8±0.6 0.3±0.7 NY-NJ-CT-PA CMSA 29 4.2±1.5 4.3±1.8 1.3±1.2 1.2±1.5 1.1±1.5 4.1±1.7 0.5±0.7 0.6±0.8 Other CMSA 185 4.4±1.4 4.4±1.5 1.2±1.2 1.7±2.6 1.2±2.0 4.4±1.7 0.5±0.8 0.6±0.8 Non-CMSA 22 4.3±1.8 4.3±1.8 1.3±1.1 1.9±3.6 1.3±2.8 4.4±1.8 0.4±0.8 0.7±0.9 Total 246 4.4±1.5 4.4±1.5 1.2±1.1 1.6±2.5 1.2±2.0 4.3±1.7 0.5±0.8 0.6±0.8 P-value 0.0599 0.0635 0.7858 0.0426 0.0561 0.0749 0.535 0.6734

INTRODUCTION:Descent of the ureter into the inguinal canal or scrotum is rare but undoubtedly underreported. Most known cases were recognized at the time of surgery for hernia repair. We encountered five cases recently. PRESENTATION OF CASE:We reviewed the records and CT images of five patients with inguinal hernias containing a segment of the ureter. All of our cases, like most reported cases, featured obese adult males. Our cases had different outcomes, ranging from inadvertent injury of the displaced ureter to correction of the anomaly at the time of hernia repair. DISCUSSION:In all of our cases, the affected ureter was displaced anteriorly from the psoas muscle by greater than 1cm at the level of the L4 vertebra on abdominal CT. This association has not been previously described. CONCLUSION:Pre-operative diagnosis by CT can prevent injury to the ureter. We hypothesize that anterior displacement of the ureter at the level of L4 as seen on CT may be predictive of inguinoscrotal herniation of the ureter.

Objective: We aimed to determine whether the variability in surveillance strategies after curativeintent primary treatment of ovarian cancer is related to practitioner age. Materials and Methods:The 943 members of The Society of Gynecologic Oncology (SGO) were surveyed by conventional mail to quantify their surveillance strategies for patients with ovarian carcinoma after potentially curative initial treatment.We requested data regarding the recommended frequency of 10 commonly employed surveillance modalities.Age was used as a proxy for time since formal residency training.Results: There were 283 responders: 58 were aged 30-39, 114 were aged 40-49, 70 were aged 50-59, and 41 were aged ≥ 60.Older gynecologic oncologists (60+) ordered office visits and pelvic examinations more frequently than younger gynecologic oncologists in year 1 (p<0.05).They Original Research Articleordered comprehensive metabolic panels more frequently during years 2-4 (p<0.05).They ordered CBCs more frequently during years 1-5 and year 10.Conclusions: Although we had predicted that younger physicians would order surveillance tests more frequently than older physicians, we found the opposite.However, the differences attributable to age were clinically small.The results suggest that physician age does not account for a large portion of the known overall variation in the clinical practice of ovarian cancer patient surveillance after initial treatment.We propose that continuing medical education is a factor that can most plausibly explain this.

ABSTRACTRegular consumption of moderate amounts of ethanol has important health benefits on atherosclerotic cardiovascular disease (ASCVD). Overindulgence can cause many diseases, particularly alcoholic liver disease (ALD). The mechanisms by which ethanol causes both beneficial and harmful effects on human health are poorly understood. Here we demonstrate that ethanol enhances TGF‐β‐stimulated luciferase activity with a maximum of 0.5–1% (v/v) in Mv1Lu cells stably expressing a luciferase reporter gene containing Smad2‐dependent elements. In Mv1Lu cells, 0.5% ethanol increases the level of P‐Smad2, a canonical TGF‐β signaling sensor, by ∼2‐3‐fold. Ethanol (0.5%) increases cell‐surface expression of the type II TGF‐β receptor (TβR‐II) by ∼2‐3‐fold from its intracellular pool, as determined by I125‐TGF‐β‐cross‐linking/Western blot analysis. Sucrose density gradient ultracentrifugation and indirect immunofluorescence staining analyses reveal that ethanol (0.5% and 1%) also displaces cell‐surface TβR‐I and TβR‐II from lipid rafts/caveolae and facilitates translocation of these receptors to non‐lipid raft microdomains where canonical signaling occurs. These results suggest that ethanol enhances canonical TGF‐β signaling by increasing non‐lipid raft microdomain localization of the TGF‐β receptors. Since TGF‐β plays a protective role in ASCVD but can also cause ALD, the TGF‐β enhancer activity of ethanol at low and high doses appears to be responsible for both beneficial and harmful effects. Ethanol also disrupts the location of lipid raft/caveolae of other membrane proteins (e.g., neurotransmitter, growth factor/cytokine, and G protein‐coupled receptors) which utilize lipid rafts/caveolae as signaling platforms. Displacement of these membrane proteins induced by ethanol may result in a variety of pathologies in nerve, heart and other tissues. J. Cell. Biochem. 117: 860–871, 2016. © 2015 Wiley Periodicals, Inc.

e21511 Background: Case reports have suggested that rosacea (and particularly rhinophyma, a consequence of rosacea), might cause angiosarcoma (AS) or lymphangiosarcoma (LAS) in rosacea-affected sites. As in Stewart-Treves syndrome, AS/LAS in rosacea-affected sites features lymphatic obstruction, edema, prominent varicose veins, and other features of chronic inflammation. No reports aiming to quantitatively establish a causal relationship have been published, to our knowledge. Recent evidence points to an aberrant innate immune response, mediated by altered endogenous polypeptides known as cathelicidins, as a primary pathogenic event in rosacea. Cathelicidins are proinflammatory and vasoactive agents that cause the prominent inflammation in rosacea. It is thus plausible that rosacea is an authentic risk factor for AS and LAS. We sought to carry out a population-based analysis to confirm or refute an association between rosacea and sarcoma. Methods: IRB approval was obtained. We abstracted pertinent data from the records of patients with head and neck sarcomas of all subtypes. We requested and received data from Roswell Park Cancer Institute and calculated the crude odds ratio for this classic case-control study. Results: We received record abstractions from 228 patients spanning years 1969-2012. We excluded the 30 cases of Kaposi’s sarcoma, Ewing’s sarcoma, sarcomas not in the head and neck region, and carcinomas. We included 198 soft tissue and skeletal cases with head and neck sarcomas of all subtypes. The calculated odds ratio was 11.9 (95% confidence interval 1.05, 136.0). Thus, the odds of having a history of rosacea were 11.9 times greater than for subjects with AS or LAS than for all other soft tissue or skeletal sarcomas. Conclusions: Ours is the first analysis designed to detect an association between rosacea and head and neck angiosarcoma and lymphangiosarcoma, as far as we know. An association was demonstrated, but the confidence interval is wide. We seek access to additional large data sets suitable for analysis. Rosacea No rosacea Total Angiosarcoma or lymphangiosarcoma cases 2 28 30 All other soft tissue or skeletal sarcoma cases 1 167 168 Total 3* 195 198 * All three were in sites where rosacea commonly occurs.

e16530 Background: Over 21,000 women are diagnosed with ovarian cancer in the US annually. Most patients receive curative-intent treatment. Post-treatment surveillance is commonly done. We have previously documented dramatic variation in surveillance intensity among members of the Society of Gynecologic Oncologists (SGO). Several large professional organizations have offered consensus-based surveillance guidelines. However, none are based on high quality-evidence. It is commonly believed that health maintenance organizations (HMOs) restrict test utilization. We sought to determine the effect of HMO penetration rate on the known variation in surveillance strategies. Methods: 943 SGO members and candidate members were surveyed regarding their surveillance practices. Members were asked to consider 4 idealized clinical vignettes and indicate their surveillance plan for each. A menu of 11 testing modalities was offered. Practice patterns were stratified by HMO penetration rate (0-29%, 30-40%, >40%) in each physician’s practice location. Repeated-measures ANOVA was employed for analysis. Results: Of the SGO members and candidate members surveyed, 323 responded; 283 were evaluable. The modalities most frequently recommended were office visit, pelvic exam, and serum CA-125 level. There was significant variation (p<0.05) for these most frequently recommended modalities, but in no other modalities. For example, in year 1, pelvic exam was recommended 4.4 ± 1.6 (mean ±SD) times for the 0-29% penetration rate cohort and 4.2 ± 1.2 times for the 30-40% cohort. Conclusions: We found little evidence that HMOs restrict test utilization. The HMO penetration rate in the clinician’s practice location cannot account for the overall variation we have documented previously.

Johnson, Frank E. MD, FACS; Wu, Daniel Z. BS; Allam, Emad S. MD; Margenthaler, Julie A. MD; Virgo, Katherine S. PhD; Chen, Ling PhD Author Information