Stroma-derived neoplasms and pseudoneoplastic lesions of the spleen: a select review of pathologic and CT/MRI findings.

A wide spectrum of benign and malignant primary mesenchymal tumors and tumor-like lesions of the spleen has been recently included under the umbrella term 'stroma-derived' neoplasms and tumor-like lesions. These include dendritic cell neoplasms such as follicular dendritic cell sarcoma, EBV-positive inflammatory follicular dendritic cell sarcoma, and fibroblastic reticular cell tumor; smooth muscle and myofibroblastic lesions such as inflammatory pseudotumor, EBV-associated smooth muscle tumor and undifferentiated pleomorphic sarcoma as well as a diverse spectrum of vascular and vascular-stromal tumors and tumor-like lesions. While some tumor and tumor-like lesions are unique to the spleen, others may also occur in diverse extra-splenic viscera. These tumors and tumor-like lesions demonstrate characteristic histopathology, immunocytochemistry and biological behavior. While cross-sectional imaging studies allow detection, staging and limited characterization of these splenic lesions, histopathological confirmation permits optimal management and surveillance strategies.

The many faces of ectopic pregnancies: demystifying the common and less common entities.

Ectopic pregnancy is a major cause of 1st trimester pregnancy deaths. It occurs in various locations in the abdominopelvic cavity. Ultrasonography is a first-line, rapid, and noninvasive modality for ectopic pregnancy evaluation. MRI can help clarify equivocal cases. When in doubt about the location, one should give an intrauterine pregnancy the benefit of the doubt with close ultrasound and hCG follow-up. Here, we will review the imaging findings and mimickers of ectopic pregnancies.

Correlating computed tomography pulmonary angiography signs of right ventricular strain in pulmonary embolisms to clinical outcomes.

INTRODUCTION: Right ventricular strain (RVS) in pulmonary embolism (PE) can be used to stratify risk and direct intervention. The clinical significance of computed tomography pulmonary angiogram (CTPA)-derived radiologic signs of RVS, however, remains incompletely characterized. We retrospectively analyzed a cohort of persons with acute PE to determine which, if any, findings of RVS on CTPA correlate with clinical outcomes. METHODS: All patients with PE diagnosed on CTPA from March 2013 through February 2015 at Lyndon B. Johnson Hospital were identified. Their records were retrospectively reviewed to identify length of stay, intensive care unit (ICU) placement, hemodynamic failure, use of thrombolytics, vasopressor requirement, mechanical ventilation, and attributable mortality. Three radiologists, blinded to clinical outcomes, separately reviewed the cohort's CTPAs to identify signs of RVS - pulmonary trunk size, internal size of the right and left ventricles, paradoxical interventricular septal bowing, inferior vena cava (IVC) contrast reflux, and hepatic vein contrast reflux. RESULTS: In our cohort of 102 persons, 12 demonstrated hemodynamic failure, 13 required ICU placement, 3 received thrombolysis, and 5 had death attributable to PE. The greatest interobserver agreement among radiologists existed for the presence of increased pulmonary trunk size (0.76 kappa by %agreement) and hepatic vein contrast reflux (0.92 kappa by %agreement). A multiple regression analysis found that when 100% radiologist agreement existed, presence of paradoxical intravenous septal bowing predicted thrombolytic usage (P = 0.02), and the presence of IVC reflux predicted attributable mortality (P = 0.03). CONCLUSION: Only IVC contrast reflux was associated with increased mortality, and no other sign of RVS on CTPA correlated with clinical outcomes. This suggests that most signs of RVS on CTPA do not reliably predict PE severity. Therefore, RVS seen by CTPA should be used cautiously in weighing the decision to initiate thrombolytics.

Wisdom Tooth's Revenge: Retropharyngeal Abscess and Mediastinitis after Molar Tooth Extraction.

Retropharyngeal abscess is potentially associated with high morbidity and mortality as a result of its direct anatomical connection with the mediastinum. Therefore, knowledge of the relevant anatomy is essential for recognizing the presence and extent of disease in a timely manner. In this case report, we aim to review the pertinent anatomy and patterns of spread of infection from a full blown deep neck space infection to result in mediastinitis and empyema.

Computed tomography in ventral hernia diagnosis: have we improved? A quality improvement initiative.

BACKGROUND: Previous studies suggest that agreement between readers of computed tomography (CT) scans for the diagnosis of a ventral hernia (VH) is poor (32% agreement, κ = 0.21). Recommendations were developed by surgeons and radiologists after determining common reasons for disagreement among CT reviewers; however, the long-term effect of adoption of these recommendations has not been assessed. The aim of this quality improvement (QI) project was to determine whether the incorporation of recommendations developed by surgeons and radiologists improves agreement among reviewers of CT scans in diagnosing a VH. METHODS: A prospective cohort of patients, with a CT scan of the abdomen and pelvis in the past 1 y, attending a surgery clinic at a single institution was enrolled. Enrolled subjects underwent a standardized physical examination by a trained hernia surgeon to determine the likelihood of a clinical VH (no, indeterminate, or yes). The QI intervention was the distribution and implementation of previously described recommendations. After a year of intervention, independent radiologists assessed patients' CT scans for the presence or absence of a VH. Percent agreement and kappa were calculated to determine interobserver reliability. In-person discussion on scans with disagreement was held, and the results were used as a "gold standard" to calculate sensitivity, specificity, positive, and negative predictive values for CT scan diagnosis of a VH. RESULTS: A total of 79 patients were included in the study. After QI intervention, seven radiologists agreed on 43% of the scans, and κ was 0.50 (P < 0.001). Agreement was highest among patients with a high clinical likelihood of a VH and lowest among patients with an indeterminate clinical likelihood. Sensitivity and specificity were 0.369 and 0.833, respectively. CONCLUSIONS: After the implementation of recommendations, there is improved agreement among radiologists reading CT scans for the diagnosis of a VH. However, there is substantial room for improvement, and CT scans for the diagnosis of VH is not ready for widespread use.

Inflammatory Myofibroblastic Tumors: Current Update.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biological potential with a predilection for the lung and abdominopelvic region. IMT represents the neoplastic subset of the family of inflammatory pseudotumors, an umbrella term for spindle cell proliferations of uncertain histogenesis with a variable inflammatory component. IMTs show characteristic fasciitis-like, compact spindle cell and hypocellular fibrous histologic patterns and distinctive molecular features. Imaging findings reflect pathologic features and vary from an ill-defined, infiltrating lesion to a wellcircumscribed, soft tissue mass owing to variable inflammatory, stromal, and myofibroblastic components.

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis.

UNLABELLED: The orphan nuclear hormone receptor small heterodimer partner (SHP) regulates the expression of several genes involved in bile acid homeostasis in the liver. Because bile acid toxicity is a major source of liver injury in cholestatic disease, we explored the role of SHP in liver damage induced by common bile duct ligation (BDL). Shp(-/-) mice show increased sensitivity in this model of acute obstructive cholestasis, with greater numbers of bile infarcts and higher mortality than wild-type C57BL/6 mice. This increased sensitivity could not be accounted for by differences in expression of bile acid homeostatic genes 2 or 5 days after BDL. Instead, higher basal expression of such genes, including the key biosynthetic enzyme cholesterol 7alpha hydroxylase (Cyp7A1) and the bile salt export pump, is associated with both an increase in bile flow prior to BDL and an increase in acute liver damage at only 1.5 hours after BDL in Shp(-/-) mice, as shown by bile infarcts. At 3 hours, Cyp7A1 expression still remained elevated in Shp(-/-) with respect to wild-type mice, and the hepatic and serum bile acid levels and total hepatobiliary bile acid pool were significantly increased. The increased sensitivity of mice lacking SHP contrasts with the decreased sensitivity of mice lacking the farnesoid X receptor (FXR; nuclear receptor subfamily 1, group H, member 4) to BDL, which has been associated with decreased intraductal pressure and fewer bile infarcts. CONCLUSION: We propose that differences in acute responses to BDL, particularly the early formation of bile infarcts, are a primary determinant of the differences in longer term sensitivity of the Fxr(-/-) and Shp(-/-) mice to acute obstructive cholestasis.

The environmental estrogen, nonylphenol, activates the constitutive androstane receptor.

Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription-PCR of Cyp2b10 transcript levels. CAR-null (CAR -/-) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.

Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation.

The nuclear receptor LRH-1 (NR5A2) functions to regulate expression of a number of genes associated with bile acid homeostasis and other liver functions, but mechanisms that modulate its activity remain unclear. We have found that mitogenic stimuli, including treatment with phorbol myristate (PMA), increase LRH-1 transactivation. This response maps to the hinge and ligand binding domains of LRH-1 and is blocked by the mitogen-activated protein kinase ERK1/2 inhibitor U0126. LRH-1 is a phosphoprotein and hinge domain serine residues at 238 and 243 are required for effective phosphorylation, both in vitro and in cells. Preventing phosphorylation of these residues by mutating both to alanine decreases PMA-dependent LRH-1 transactivation and mimicking phosphorylation by mutation to positively charged aspartate residues increases basal transactivation. Although serine phosphorylation of the hinge of SF-1 (NR5A1), the closest relative of LRH-1, confers a similar response, the specific targets differ in the two closely related orphan receptors. These results define a novel pathway for the modulation of LRH-1 transactivation and identify specific LRH-1 residues as downstream targets of mitogenic stimuli. This pathway may contribute to recently described proliferative functions of LRH-1.

Cdc25B as a steroid receptor coactivator.

The traditional role of the Cdc25 family of dual-specificity phosphatases is to activate cyclin-dependent kinases (CDKs) to enable progression through the cell cycle. This chapter reports that in addition to its cell cycle role, Cdc25B functions as a novel steroid receptor coactivator (SRC). When overexpressed in transgenic mammary glands, Cdc25B can up-regulate the expression of two estrogen receptor (ER)-target genes: cyclin D1 and Lactoferrin. In addition, when coexpressed with ER, Cdc25B can coactivate an ER-dependent reporter in the presence of estradiol. The coactivation of Cdc25B can be extended to the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). Because of the respective importance of ER and AR in breast and prostate cancer, this chapter focuses on the coactivation of both receptors by Cdc25B. We demonstrate that Cdc25B can interact directly with these nuclear receptors, recruit and enhance the activity of histone acetyltransferases (HATs), and potentiate cell-free transcription independent of its cell cycle regulatory function. Furthermore, because Cdc25B is up-regulated in highgrade and poorly differentiated prostate tumors, which are likely transiting from the hormone-dependent to hormone-independent state, we hypothesize that the coactivation of AR by Cdc25B may induce genes responsible for this progression. Taken together, it is highly conceivable that Cdc25B can promote neoplasia by its two disparate functions of (1) coactivation to induce higher levels of expression of steroid receptor target genes and (2) its role of activating CDKs to deregulate progression of the cell cycle, DNA replication, and mitosis.

Steroid receptor RNA activator stimulates proliferation as well as apoptosis in vivo.

Steroid receptor RNA activator (SRA) is an RNA that coactivates steroid hormone receptor-mediated transcription in vitro. Its expression is strongly up-regulated in many human tumors of the breast, uterus, and ovary, suggesting a potential role in pathogenesis. To assess SRA function in vivo, a transgenic-mouse model was generated to enable robust human SRA expression by using the transcriptional activity of the mouse mammary tumor virus long terminal repeat. Transgenic SRA was expressed in the nuclei of luminal epithelial cells of the mammary gland and tissues of the male accessory sex glands. Distinctive evidence for SRA function in vivo was obtained from the elevated levels of estrogen-controlled expression of progesterone receptor in transgenic mammary glands. Although overexpression of SRA showed strong promoting activities on cellular proliferation and differentiation, no alterations progressed to malignancy. Epithelial hyperplasia was accompanied by increased apoptosis, and preneoplastic lesions were cleared by focal degenerative transformations. In bitransgenic mice, SRA also antagonized ras-induced tumor formation. This work indicates that although coactivation of steroid-dependent transcription by SRA is accompanied by a proliferative response, overexpression is not in itself sufficient to induce turmorigenesis. Our results underline an intricate relationship between the different physiological roles of steroid receptors in conjunction with the RNA activator in the regulation of development, tissue homeostasis, and reproduction.

Complex effects of rexinoids on ligand dependent activation or inhibition of the xenobiotic receptor, CAR.

BACKGROUND: CAR/RXR heterodimers bind a variety of hormone response elements and activate transcription in the absence of added ligands. This constitutive activity of murine CAR can be inhibited by the inverse agonist ligand androstanol or increased by the agonist TCPOBOP. RXR agonists activate some RXR heterodimer complexes, which are termed permissive, while other non-permissive complexes are not responsive to such ligands. RESULTS: Direct protein-protein interaction studies demonstrate that the RXR agonist 9-cis-RA increases interaction of CAR/RXR heterodimers with the coactivator SRC-3, but also inhibits the ability of TCPOBOP to increase and androstanol to decrease coactivator binding. CAR transactivation of a response element with a five nucleotide spacer (DR-5) is unaffected by 9-cis-RA or the synthetic RXR agonist LG1069. In agreement with the inhibitory effect observed in vitro, these rexinoids block both the TCPOBOP mediated transactivation of this element and the androstanol dependent inhibition. In contrast, CAR transactivation of other response elements is increased by rexinoids. Stable expression of CAR in a HepG2 derived cell line increases expression of the endogenous CAR target CYP2B6. This expression is further increased by TCPOBOP but decreased by either androstanol or LG1069, and LG1069 blocks the stimulatory effect of TCPOBOP but not the inhibitory effect of androstanol. CONCLUSION: We conclude that CAR/RXR heterodimers are neither strictly permissive nor non-permissive for RXR signaling. Instead, rexinoids have distinct effects in different contexts. These results expand the potential regulatory mechanisms of rexinoids and suggest that such compounds may have complex and variable effects on xenobiotic responses.

Induction of bilirubin clearance by the constitutive androstane receptor (CAR).

Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice.

Functional analysis of cyclin D2 and p27(Kip1) in cyclin D2 transgenic mouse mammary gland during development.

Two mammary gland phenotypes were detected in pregnant MMTV-cyclin D2 transgenic mice; line D2-53 exhibited a lack of alveologenesis and failure to nurse, whereas line D2-58 featured a reduction in alveologenesis, but retained normal nursing behavior. In pregnant mammary glands, cyclin D2 protein levels were twofold (P<0.107) and 3.8-fold (P<0.0076) higher in line D2-58 and D2-53, respectively, compared to wild type. Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2-58 mice. Because cyclin D1 is a critical molecule in normal mammary lobuloalveolar development, these data suggest that overexpression of cyclin D2 may block mammary lobuloalveolar development through inhibition of cyclin D1 phosphorylation. During mammary gland development, p27(kip1) protein level oscillated in a similar profile in wild type and cyclin D2 transgenic mice, but was consistently higher in the cyclin D2 mice suggesting that p27(kip1) functions downstream of cyclin D2. The ratio of p27(kip1)-cdk4/p27(kip1)-cdk2 was 6.5-fold (P<0.0003) higher in cyclin D2 mammary glands compared to wild type in pregnant animals. This ratio reversed to 2.2-fold (P<0.005) higher in wild type compared to cyclin D2 mammary glands in involution suggesting that overexpression of cyclin D2 moderately induced apoptosis during pregnancy but accelerated involution. Collectively, the effects of cyclin D2 overexpression on mammary gland development during pregnancy and involution are attributed to two major factors, altered p27(kip1) protein level and inhibition of cyclin D1 phosphorylation.

Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR.

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.

Inducible expression of FGF-3 in mouse mammary gland.

Fibroblast growth factor-3 (FGF-3) is a crucial developmental regulator. Aberrant activation of this gene by mouse mammary tumor virus insertion results in pregnancy-responsive mammary tumorigenesis. To characterize better FGF-3 function in postnatal mammary gland development and cancer initiation/progression, we used a mifepristone (RU486)-inducible regulatory system to express conditionally FGF-3 in the mammary epithelium of transgenic mice. Ectopic overexpression of FGF-3 in pubescent mammary glands elicited severe perturbations in early mammary gland development leading to mammary hyperplasia. Ductal elongation was retarded, multiple cysts persisted in the virgin ducts, and ductal epithelium was expanded and multilayered. The altered ductal architecture and the persistence of hyperplastic multilayered epithelium reflect a defect in growth regulation, which resulted from an imbalance between mitogenic and apoptotic signals. By altering the duration of RU486 treatment, we showed that the persistence of mitogenic signal elicited by FGF-3 is crucial for the initiation, progression, and maintenance of the hyperplastic characteristic of the mammary epithelium. The manifestations elicited by FGF-3 could be reversed by RU486 withdrawal. In addition, synergism between the stimulus from estrogen and FGF-3 mitogenic pathways was evident and likely contributes to the pregnancy-dependent tumorigenesis of FGF-3. Taken together, the mifepristone-inducible regulatory system provides a powerful means for understanding the diverse roles of FGF-3 and its interactions with hormones in mammary gland tumorigenesis.

Redundant pathways for negative feedback regulation of bile acid production.

The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.

Ectopic expression of FGF-3 results in abnormal prostate and Wolffian duct development.

To evaluate the effects of FGF-3 expression in the prostate and male reproductive tract, we employed a bitransgenic system to target FGF-3 to these organs. We present a first study that ectopic FGF-3 expression resulted in exuberant hyperplasia of all bigenic prostatic lobes typified by epithelial stratification, cribiform structures and papillary tufts. These cells displayed increased nuclear-to-cytoplasmic ratios and bromodeoxyuridine (BrdU) proliferative index but retained relatively uniform nuclear androgen receptor (AR) and the tumor suppressor C-CAM1 staining. Furthermore, the dysmorphogenic prostatic cells also resembled PIN (prostatic intraepithelial neoplasia)-like lesions but did not appear to have invaded the basal lamina. In addition to these phenotypes, profound disorders of the bigenic Wolffian duct derivatives were observed. The bigenic ampullary glands and vas deferens were extremely cystic, hypertrophic and hyperplastic; the enlarged epididymi showed a reduction of spermatozoa and the seminal vesicles exhibited a dramatic reduction of seminal secretions. Because of these severe abnormalities, these infertile males presented with diaphragmatic hernias, hemoperitoneum and many secondary abnormalities at sacrifice. Taken together, we show that ectopic FGF-3 expression severely perturbs normal prostate development and our system should be useful for the analyses of early changes in prostatic hyperplasia.