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Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2- and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst-lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT-B and -A. Notably, increased Notch signaling in cyst-lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) genes in adult mouse models of ADPKD attenuates severity of PKD and PLD. Here we examine the role of deletion of IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knock-out mice. Perinatal deletion of Thm1 results in disorganized and expanded biliary regions, biliary fibrosis, shortened primary cilia on CK19+ biliary epithelial cells, and reduced Notch signaling. In contrast, perinatal deletion of Pkd2 causes PLD, with multiple CK19+ biliary epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knock-out mice increased hepatomegaly and liver necrosis, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 in adult mice, alone and together with Pkd2, did not cause a biliary phenotype nor affect Pkd2-mutant PLD, respectively. However, similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2-mutant cyst-lining cholangiocytes. Taken together, Thm1 is required for biliary tract development, likely by enabling Notch signaling, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not affect hepatic cystogenesis, suggesting divergent regulation of signaling and cystogenic processes in the liver by IFT-B and –A. Notably, increased Notch signaling in cyst-lining cholangiocytes may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target.

Deletion of murine Thm1, an intraflagellar transport A (IFT-A) component that mediates ciliary protein trafficking, causes hyperphagia, obesity, and metabolic syndrome. The role of Thm1 or IFT-A in adipogenesis and insulin sensitivity is unknown. Here, we report that Thm1 knockdown in 3T3-L1 pre-adipocytes promotes adipogenesis and enhances insulin sensitivity in vitro. Yet, pre-obese Thm1 conditional knockout mice show systemic insulin resistance. While insulin-induced AKT activation in Thm1 mutant adipose depots and skeletal muscle are similar to those of control littermates, an attenuated insulin response arises in the mutant liver. Insulin treatment of control and Thm1 mutant primary hepatocytes results in similar AKT activation. Moreover, pair-feeding Thm1 conditional knockout mice produces a normal insulin response, both in the liver and systemically. Thus, hyperphagia caused by a cilia defect, induces hepatic insulin resistance via a non-cell autonomous mechanism. In turn, hepatic insulin resistance drives systemic insulin resistance prior to an obese phenotype. These data demonstrate that insulin signaling across cell types is regulated differentially, and that the liver is particularly susceptible to hyperphagia-induced insulin resistance and a critical determinant of systemic insulin resistance.

The ciliopathies Bardet-Biedl Syndrome and Alström Syndrome are genetically inherited pleiotropic disorders with primary clinical features of hyperphagia and obesity. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood (Thm1 cko). Thm1 cko mice show decreased hypothalamic pro-opiomelanocortin expression as well as hyperphagia, obesity, metabolic disease and hepatic steatosis. In obese Thm1 cko mice, two-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied with decreased levels of blood glucose, insulin and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report of MetAP2i reducing hyperphagia and body weight, and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.

To determine if elevated markers of poor glycemic control (HgA1c and fasting glucose levels) in patients surgically staged for type I endometrial cancer is related to a higher stage or higher grade at the time of diagnosis. Also, to assess if these markers impact overall survival. A retrospective chart review was performed from January 2000 to June 2010 at three academic medical centers. Patients were included if they underwent surgical staging and had HgA1c drawn within 3 months before surgery. Demographic data, fasting blood glucose levels and overall survival data were also obtained. Eighty-two patients fitting the inclusion criteria were identified during the study period. There was a strong positive correlation between HgA1c and fasting glucose. There was no statistical difference with regard to stage alone, grade alone, or when stratified together with regard to HgA1c or fasting glucose levels. There was a trend toward increased mean HgA1c across increasing stages, but this was not statistically significant. Diabetes, HgA1c and tumor grade did not affect overall survival, but advanced stage was a poor prognostic measure for overall survival. Elevated preoperative HgA1c has a trend toward a higher stage at the time of diagnosis. Advanced stage is a poor prognostic measure for overall survival.

To determine whether hydronephrosis is an independent prognostic indicator of survival among patients with advanced cervical carcinoma. Moreover, we wanted to demonstrate the relationship between unilateral and bilateral hydronephrosis and overall survival.Retrospective analysis of 197 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB cervical carcinoma or higher treated between 1990 and 2007 was conducted. Inclusion criteria were clinical staging according to FIGO criteria, standardized radiation treatment and cisplatin-based chemosensitization regimens. Associations between hydronephrosis and covariates-age, race, histopathologic diagnosis, pelvic sidewall involvement, stage, nodal involvement, and Gynecologic Oncology Group/Eastern Cooperative Oncology Group performance status (PS)-were determined. Statistical analysis including Kaplan-Meier, log-rank test, proportional hazards regression, Fisher exact test, and Mann-Whitney test were used where appropriate, with P0.05 considered significant.Of 143 included patients, 73 patients had no hydronephrosis (HN), 39 patients had unilateral HN, and 31 patients had bilateral HN. Twenty-nine patients (40%) with no HN died compared to 24 patients (61.5%) with unilateral HN and 21 patients (67.7%) with bilateral HN. Median time to death was significantly shorter for patients with unilateral HN (27 months; 95% confidence interval [CI], 10-48) and bilateral HN (12 months; 95% CI, 6-23) versus patients without HN (68 months; 95% CI, 39-∞; P0.001). Unadjusted hazard ratio (HR) for HN (both unilateral and bilateral) was 2.4 (95% CI, 1.5-3.8); P0.001. Of potential covariates evaluated, PS and sidewall involvement were significantly associated with HN (P = 0.021 and P = 0.014, respectively). Proportional hazards regression revealed that controlling for use of radiation, chemotherapy, and for PS, HN was still significantly associated with poor prognosis (HR unilateral HN = 2.0, 95% CI, 1.2-3.5; HR bilateral HN = 3.2, 95% CI, 1.7-6.0); P ≤ 0.001.Hydronephrosis is an independent poor prognostic indicator of survival in patients with advanced cervical cancer. Bilateral hydronephrosis compared to unilateral involvement confers a worse overall prognosis. Additional studies are needed to determine if FIGO staging should be amended.

Objectives The purpose of this study is to detect differences in overall survival between the 1988 FIGO staging and current staging of uterine carcinosarcomas to determine if revised 2009 staging accurately predicts actual patient survival. Methods From 1988 until 2010, patients with uterine carcinosarcoma were retrospectively identified from tumor registry records. Patients were grouped in both broad stages (1–4) and all FIGO substages in order to detect differences. Time-dependant receiver operating characteristic curves (ROC) were generated to predict death before the end of the second year post-diagnosis for both the new and revised system. Kaplan Meier estimated median survival time was utilized to compare actual patient survival. Results Of 112 patients with carcinosarcoma, 37 patients (33%) had FIGO Stage I disease, 15 patients (13.4%) had Stage II disease, 36 patients (32%) were diagnosed as Stage III, and 24 patients (21.4%) had Stage IV disease. 106 of 112 (94.6%) patients underwent lymphadenectomy (pelvic +/− para-aortic). Four patients (3.6%) were downstaged when utilizing broad staging criteria: 2 patients were downstaged from Stage II to I, and 2 patients were downstaged from Stage III to Stage I and II respectively. When looking at substage, the area under the ROC was 0.67 for the former staging system, and 0.65 for the revised staging. Kaplan–Meier estimated median survival time post-diagnosis was 610days (95% CI [478,930]). Conclusion Based upon our reclassification of 112 patients with uterine carcinosarcoma, the revised FIGO staging system does not predict survival more accurately than former staging. Carcinosarcoma has an overall poor prognosis and better indicators of survival are needed.

e15570 Background: To test the validity of a MSKCC nomogram for predicting overall survival in black women with uterine cancer. Methods: Retrospective review of a uterine cancer database at two maj...

We aimed to evaluate the role of early metabolic response in the management of patients with metastatic seminoma. A significant association was found between early metabolic response and tumor shrinkage at the end of chemotherapy. Simplifying the radiologic follow-up for early metabolic complete responders was an end point. Partial responders included patients with difficult-to-treat disease. Background: In patients with metastatic seminoma, designing a risk-adapted strategy that may help personalize the burden of treatment and follow-up is required. Patients and Methods: Patients who were administered cisplatin, etoposide, and bleomycin (PEB) were staged at baseline with computed tomography (CT), positron emission tomography (PET), and serum tumor markers. Restaging was then performed with PET after 2 cycles of PEB (PET2) and with CT after 3 to 4 cycles of treatment. The 20% cutoff of maximal standardized uptake value (SUVmax) changes and Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were applied to define the response. The Wilcoxon rank sum test was used to analyze the association between metabolic response and the shrinkage of target lesions. Results: Between February 2009 and November 2013, 37 patients were enrolled. After 2 cycles of PEB, 27 patients (72.9%; 95% confidence interval [CI], 55.8-86.2) had a metabolic complete response (CR) and 10 patients had a partial response (PR; 27%; 95% CI, 13.8-44.1). A significant association was found between PET2 response and baseline (P = .003), final diameter (P < .001), and percentage of tumor shrinkage (P = .014) of target lesions. After 18 months' (interquartile range [IQR], 13-23) median follow-up, 2 patients with PET2 PR had relapsed disease; none of those with a CR had relapsed disease. Conclusions: A significant association was found between early metabolic response and tumor shrinkage in patients with advanced seminoma. Patients achieving a PET2 CR could be predicted not to need additional treatment after PEB, and simplifying their follow-up should be an end point. PET2 might also identify difficult to treat cases at an early stage. (C) 2015 Elsevier Inc. All rights reserved.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus