Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium

Most high‐grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal‐type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal‐type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi‐lineage differentiation and can form glands with tubal‐type epithelium. We used double transgenic Ovgp1‐iCreERT2;R26RLSL‐eYFP mice, which express an eYFP reporter protein in OVGP1‐positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post‐TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM‐treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post‐TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM‐treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre‐pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151844/1/path5308.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151844/2/path5308-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151844/3/path5308_am.pd

High‐grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease

Recent studies have suggested that the most common and lethal type of ‘ovarian’ cancer, i.e. high‐grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium. We have developed Ovgp1‐iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen‐regulated Cre recombinase in oviductal epithelium – the murine equivalent of human fallopian tube epithelium (FTE). We employed Ovgp1‐iCreERT2 mice to show that FTE‐specific inactivation of several different combinations of tumour suppressor genes that are recurrently mutated in human HGSCs – namely Brca1, Trp53, Rb1, and Nf1 – results in serous tubal intraepithelial carcinomas (STICs) that progress to HGSC or carcinosarcoma, and to widespread metastatic disease in a subset of mice. The cancer phenotype is highly penetrant and more rapid in mice carrying engineered alleles of all four tumour suppressor genes. Brca1, Trp53 and Pten inactivation in the oviduct also results in STICs and HGSCs, and is associated with diffuse epithelial hyperplasia and mucinous metaplasia, which are not observed in mice with intact Pten. Oviductal tumours arise earlier in these mice than in those with Brca1, Trp53, Rb1 and Nf1 inactivation. Tumour initiation and/or progression in mice lacking conditional Pten alleles probably require the acquisition of additional defects, a notion supported by our identification of loss of the wild‐type Rb1 allele in the tumours of mice carrying only one floxed Rb1 allele. Collectively, the models closely recapitulate the heterogeneity and histological, genetic and biological features of human HGSC. These models should prove useful for studying the pathobiology and genetics of HGSC in vivo, and for testing new approaches for prevention, early detection, and treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138263/1/path4927_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138263/2/path4927.pd

Characterising ‘bounce‐back’ readmissions after radical cystectomy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152623/1/bju14874.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152623/2/bju14874_am.pd

Predictors and Cost of Readmission in Total Knee Arthroplasty

BACKGROUND: The Comprehensive Care for Joint Replacement bundle was created to decrease total knee arthroplasty (TKA) cost. To help accomplish this, there is a focus on reducing TKA readmissions. However, there is a lack of national representative sample of all-payer hospital admissions to direct strategy, identify risk factors for readmission, and understand actual readmission cost. METHODS: We used the Nationwide Readmission Database to examine national readmission rates, predictors of readmission, and associated readmission costs for elective TKA procedures. We fit a multivariable logistic regression model to examine factors associated with readmission. Then, we determined mean readmission costs and calculated the readmission cost when distributed across the entire TKA population. RESULTS: We identified 224,465 patients having TKA across all states participating in the Nationwide Readmission Database. The mean unadjusted 30-day TKA readmission rate was 4%. The greatest predictors of readmission were congestive heart failure (odds ratio [OR] 2.51, 95% confidence interval [CI] 2.62-2.80), renal disease (OR 2.19, 95% CI 2.03-2.37), and length of stay greater than 4 days (OR 2.4, 95% CI 2.25-2.61). The overall median cost for each readmission was $6753 ± 175. Extrapolating the readmission cost for the entire TKA population resulted in the readmission cost being 2% of the overall 30-day procedure cost. CONCLUSIONS: A major focus of the Comprehensive Care for Joint Replacement bundle is improving cost and quality by limiting readmission rates. TKA readmissions are low and comprise a small percentage of total TKA cost, suggesting that they may not be the optimal measure of quality care or a significant driver of overall cost