Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes.

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.

Evaluation of an assessment model to reduce waitlist times for occupational therapy in a rural community health setting.

OBJECTIVE: Community occupational therapy services have seen an increase in demand over the last three years, resulting in longer waitlist times for service provision, particularly in rural areas where it is difficult to recruit experienced occupational therapists. Utilising a demand management model, the Basic Assessment Model Pre-Screening Tool was developed by a team of Occupational Therapists and allied health assistants to decrease client waitlist times at one rural community health service. DESIGN: An evaluation of the implementation of an assessment model with comparison of quantitative data pre and post intervention. SETTING: Rural Community Health Service in Victoria, Australia PARTICIPANTS: 456 clients that were registered as community-based clients requiring occupational therapy services. MAIN OUTCOME MEASURE: Following the implementation of the newly developed Basic Assessment Model the number of occupational therapy assessments increased and there was a decrease in the median wait time that clients were on the waitlist in comparison to pre implementation. RESULTS: There was a statistically significant decrease (p<0.001) in the median number of days spent on the waitlist for the post intervention group (80 days) compared to the pre intervention group (105 days). CONCLUSION: The results of this study suggest that waiting lists for community occupational therapy services can be reduced by implementing this basic assessment model ultimately improving the health outcomes of clients.

Use of fully covered self-expanding metal stents for benign biliary etiologies: a large multi-center experience.

BACKGROUND: Fully-covered self-expandable metal stents (FCSEMS) have been used in benign biliary diseases although reported data is limited. These devices are most commonly used to treat biliary leaks, strictures, or both. The aim of this study was to evaluate effectiveness of FCSEMS in treating benign biliary disease and recognize the associated complications. METHODS: We performed a multicenter longitudinal retrospective cohort study of patients with benign biliary disease needing FCSEMS between 2011 and 2016. Descriptive statistics were performed using SPSS version 24 (SPSS Inc, Chicago, IL, USA) and continuous variables were presented as mean±standard deviation. RESULTS: 75, 57% M/43% F, with a mean age of 58.5±14.9 years, were included. 64 (85%) had benign strictures, 7 patients had leaks, and 4 patients had both a leak and a stricture. Chronic pancreatitis was the most common cause of BBS (47%) and cholecystectomy was the most common cause of leaks. FCSEMS placement was technically successful in all patients. Four patients died of unrelated causes. A recurrent stricture was observed in 24 (32%) of the patients. Recurrent strictures were most commonly seen in patients with chronic pancreatitis 12/35 (34%). Stent migration occurred in 8/75 patients (10.7%). Seven patients (9.3%) had adverse events, acute pancreatitis (N.=4) was most common. CONCLUSIONS: FCSEMS are safe and effective for treating biliary strictures and leaks. We report decreased rates of stent migration compared to previous studies. Prospective studies are needed to compare plastic stents with FCSEMS, determine optimal stent in-dwell times and cost effectiveness of FCSEMS.

Efficacy, Safety, and Outcomes of Endoscopic Retrograde Cholangiopancreatography With Per-Oral Pancreatoscopy: A Multicenter Experience.

INTRODUCTION: Per-oral pancreatoscopy can be used for both evaluation and treatment of pancreatic duct stones during endoscopic retrograde cholangiopancreatography, evaluating and treating pancreatic duct strictures of indeterminate etiology, and visual inspection and direct biopsy of pancreatic duct mucosa for diagnosis of intraductal papillary mucinous neoplasm (IPMN). We aim to describe the efficacy, safety, and outcomes of pancreatoscopy in a large, multicenter series of patients. MATERIALS AND METHODS: A multicenter retrospective review was conducted of all patients who underwent per-oral pancreatoscopy at 2 large tertiary-care medical centers. Review of relevant medical records, laboratory data, imaging studies, endoscopic procedure notes, telephone follow-up notes, and progress notes was performed. RESULTS: Thirty-three patients underwent 41 pancreatoscopy procedures. Indications included: 20 (48.8%) for diagnosis and treatment of pancreatic duct stones, 16 (39%) for investigation of IPMN, and 5 (12.2%) for evaluation of pancreatic duct strictures.In 20 procedures performed for stone disease, complete pancreatic duct clearance was achieved in 17 of 20 (85%) cases. Strictures were successfully dilated in 5 of 5 (100%) procedures. Direct visualization and biopsy demonstrated IPMN in 11 of 11 (100%) cases. Adverse events occurred in 3 of 41 (7.3%) of procedures, all of which were mild. CONCLUSIONS: In this large series, we demonstrate that in patients with difficult to manage stone disease, strictures and possible malignant ductal pathology, pancreatoscopy is an effective and safe tool that can facilitate both diagnosis and effective therapy. Adverse events in our study were mild and within acceptable limits, further demonstrating that this is a safe procedure that should be offered to appropriate patients.

Prevalence of regurgitation and reingestion in orangutans housed in North American zoos and an examination of factors influencing its occurrence in a single group of Bornean orangutans.

Very little research has explored regurgitation and reingestion (R/R) in orangutans. We first aimed to determine the prevalence of R/R in the North American zoo population through a survey of accredited institutions. We report the prevalence of R/R in orangutans >4 years of age as 35% with some sex and species differences. Additionally, survey respondents reported fruit and sweet foods as the most common triggers of R/R. We also explored rates of R/R in a single group of Bornean orangutans at Cleveland Metroparks Zoo. We examined the relationship between R/R and feeding schedule and opportunistically observed rates of R/R with and without the presence of browse and sweet foods. We found evidence that R/R is associated with feeding time and that the presence of browse significantly increased the amount of time that animals spent feeding. There was a trend toward decreased R/R when browse was available. We also observed higher rates of R/R when sweet foods were available and we propose that this may have mitigated some of the beneficial effects of browse. We suggest that future studies look further at nutritional influences on R/R behavior.

Effectiveness of assisted reproductive technology (ART).

OBJECTIVES: We reviewed the evidence regarding the outcomes of interventions used in ovulation induction, superovulation, and in vitro fertilization (IVF) for the treatment of infertility. Short-term outcomes included pregnancy, live birth, multiple gestation, and complications. Long-term outcomes included pregnancy and post-pregnancy complications for both mothers and infants. DATA SOURCES: MEDLINE and Cochrane Collaboration resources. REVIEW METHODS: We included studies published in English from January 2000 through January 2008. For short-term outcomes, we excluded non-randomized studies and studies where a pregnancy or live birth rate per subject could not be calculated. For long-term outcomes, we excluded studies with fewer than 100 subjects and those without a control group. Articles were abstracted for relevant details, and relative risks or odds ratios, with 95 percent confidence intervals, were calculated for outcomes of interest for each study. RESULTS: We identified 5294 abstracts and (for the three questions discussed in this draft report) reviewed 1210 full-text articles and included 478 articles for abstraction. Approximately 80 percent of the included studies were performed outside the United States. The majority of randomized trials were not designed to detect differences in pregnancy and live birth rates; reporting of delivery rates and obstetric outcomes was unusual. Most did not have sufficient power to detect clinically meaningful differences in live birth rates, and had still lower power to detect differences in less frequent outcomes such as multiple births and complications. Interventions for which there was sufficient evidence to demonstrate improved pregnancy or live birth rates included: (a) administration of clomiphene citrate in women with polycystic ovarian syndrome, (b) metformin plus clomiphene in women who fail to respond to clomiphene alone; (c) ultrasound-guided embryo transfer, and transfer on day 5 post-fertilization, in couples with a good prognosis; and (d) assisted hatching in couples with previous IVF failure. There was insufficient evidence regarding other interventions. Infertility itself is associated with most of the adverse longer-term outcomes. Consistently, infants born after infertility treatments are at risk for complications associated with abnormal implantation or placentation; the degree to which this is due to the underlying infertility, treatment, or both is unclear. Infertility, but not infertility treatment, is associated with an increased risk of breast and ovarian cancer. CONCLUSIONS: Despite the large emotional and economic burden resulting from infertility, there is relatively little high-quality evidence to support the choice of specific interventions. Removing barriers to conducting appropriately designed studies should be a major policy goal.

Characterization of progesterone receptor isoform expression in fetal membranes.

OBJECTIVE: To quantify expression of progesterone receptor (PR) messenger RNA (mRNA) isoforms in fetal membranes, and to determine whether these levels change in culture. STUDY DESIGN: Placentas from women undergoing term cesarean delivery before labor were collected. Layers of amnion, chorion, and decidua were separated manually, enzymatically digested, and separated further with the use of a density gradient. RNA was extracted immediately and after culture for 48 hours, then analyzed by quantitative reverse transcription polymerase chain reaction for PR-A, PR-B, and beta-2 microglobulin mRNA expression. Separation of cell types was confirmed by immunohistochemistry. RESULTS: PR isoform expression was identified in fetal membranes, with levels highest in decidua and below the limits of detection in amnion. The ratio of PR-A/PR-B mRNA was not significantly different between cell layers. PR mRNA isoform levels did not differ significantly in fresh versus cultured cells. CONCLUSION: Quantitative reverse transcription polymerase chain reaction was used to quantitate expression of PR mRNA isoforms in cells of fetal membranes and to validate systems for further study of PR with respect to inflammation, infection, and preterm delivery.