MRI proton density fat fraction for estimation of tumor grade in steatotic hepatocellular carcinoma.

OBJECTIVES: Image-based detection of intralesional fat in focal liver lesions has been established in diagnostic guidelines as a feature indicative of hepatocellular carcinoma (HCC) and associated with a favorable prognosis. Given recent advances in MRI-based fat quantification techniques, we investigated a possible relationship between intralesional fat content and histologic tumor grade in steatotic HCCs. METHODS: Patients with histopathologically confirmed HCC and prior MRI with proton density fat fraction (PDFF) mapping were retrospectively identified. Intralesional fat of HCCs was assessed using an ROI-based analysis and the median fat fraction of steatotic HCCs was compared between tumor grades G1-3 with non-parametric testing. ROC analysis was performed in case of statistically significant differences (p < 0.05). Subgroup analyses were conducted for patients with/without liver steatosis and with/without liver cirrhosis. RESULTS: A total of 57 patients with steatotic HCCs (62 lesions) were eligible for analysis. The median fat fraction was significantly higher for G1 lesions (median [interquartile range], 7.9% [6.0─10.7%]) than for G2 (4.4% [3.2─6.6%]; p = .001) and G3 lesions (4.7% [2.8─7.8%]; p = .036). PDFF was a good discriminator between G1 and G2/3 lesions (AUC .81; cut-off 5.8%, sensitivity 83%, specificity 68%) with comparable results in patients with liver cirrhosis. In patients with liver steatosis, intralesional fat content was higher than in the overall sample, with PDFF performing better in distinguishing between G1 and G2/3 lesions (AUC .92; cut-off 8.8%, sensitivity 83%, specificity 91%). CONCLUSIONS: Quantification of intralesional fat using MRI PDFF mapping allows distinction between well- and less-differentiated steatotic HCCs. CLINICAL RELEVANCE: PDFF mapping may help optimize precision medicine as a tool for tumor grade assessment in steatotic HCCs. Further investigation of intratumoral fat content as a potential prognostic indicator of treatment response is encouraged. KEY POINTS: • MRI proton density fat fraction mapping enables distinction between well- (G1) and less- (G2 and G3) differentiated steatotic hepatocellular carcinomas. • In a retrospective single-center study with 62 histologically proven steatotic hepatocellular carcinomas, G1 tumors showed a higher intralesional fat content than G2 and G3 tumors (7.9% vs. 4.4% and 4.7%; p = .004). • In liver steatosis, MRI proton density fat fraction mapping was an even better discriminator between G1 and G2/G3 steatotic hepatocellular carcinomas.

Alveolar Echinococcosis in a Patient with Presumed Autoimmune Hepatitis and Primary Sclerosing Cholangitis: An Unexpected Finding after Liver Transplantation.

Primary sclerosing cholangitis is an important reason for liver transplantation. Hepatic alveolar echinococcosis (AE) is caused by Echinococcus multilocularis and presents characteristic calcified conglomerates detected by ultrasound or computed tomography scan of the liver. Symptoms of AE only occur after a long period of infection when cholestasis or cholangitis becomes apparent. Here, we report on a patient with presumed autoimmune hepatitis and primary sclerosing cholangitis. After liver transplantation, alveolar echinococcosis was diagnosed in the liver explant.

Lysine-specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) synergistically repress proinflammatory cytokines and classical complement pathway components.

Histone modifying enzymes confer epigenetic marks, directing the changes in gene expression required for diverse cellular processes. Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by demethylating histone H3 on lysine 4 and lysine 9. Analyzing transcriptomes on microarrays, we identified genes which represent inflammatory-related targets of LSD1. We demonstrate a repressive role of LSD1 in proinflammatory cytokine expression such as IL1α, IL1ß, IL6 and IL8 and classical complement components. Consistently, LSD1 occupies and regulates the promoter of these genes. In addition, we demonstrate that HDAC1 and LSD1 synergistically regulate these inflammatory-related genes. Our data reveal a novel role for LSD1 in suppressing immune responses.

The signal transducer CD24 suppresses the germ cell program and promotes an ectodermal rather than mesodermal cell fate in embryonal carcinomas.

Testicular germ cell tumors (GCTs) are stratified into seminomas and nonseminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the nonseminoma stem cell population-embryonal carcinoma (EC)-is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra-embryonic lineages (yolk sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared with other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, that is, histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3 ubiquitin ligases, or bromodomain (BRD) proteins. Additionally, three-dimensional (3D) co-cultivation of EC cells with microenvironmental cells, such as fibroblasts, and endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9 deficiency model, we demonstrate that CD24 fulfills a bivalent role in differentiation via regulation of homeobox, and phospho- and glycoproteins; that is, it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity toward cisplatin in EC cells, including cisplatin-resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.

Analysis of TET expression/activity and 5mC oxidation during normal and malignant germ cell development.

During mammalian development the fertilized zygote and primordial germ cells lose their DNA methylation within one cell cycle leading to the concept of active DNA demethylation. Recent studies identified the TET hydroxylases as key enzymes responsible for active DNA demethylation, catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine. Further oxidation and activation of the base excision repair mechanism leads to replacement of a modified cytosine by an unmodified one. In this study, we analyzed the expression/activity of TET1-3 and screened for the presence of 5 mC oxidation products in adult human testis and in germ cell cancers. By analyzing human testis sections, we show that levels of 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine are decreasing as spermatogenesis proceeds, while 5-methylcytosine levels remain constant. These data indicate that during spermatogenesis active DNA demethylation becomes downregulated leading to a conservation of the methylation marks in mature sperm. We demonstrate that all carcinoma in situ and the majority of seminomas are hypomethylated and hypohydroxymethylated compared to non-seminomas. Interestingly, 5-formylcytosine and 5-carboxylcytosine were detectable in all germ cell cancer entities analyzed, but levels did not correlate to the 5-methylcytosine or 5-hydroxymethylcytosine status. A meta-analysis of gene expression data of germ cell cancer tissues and corresponding cell lines demonstrates high expression of TET1 and the DNA glycosylase TDG, suggesting that germ cell cancers utilize the oxidation pathway for active DNA demethylation. During xenograft experiments, where seminoma-like TCam-2 cells transit to an embryonal carcinoma-like state DNMT3B and DNMT3L where strongly upregulated, which correlated to increasing 5-methylcytosine levels. Additionally, 5-hydroxymethylcytosine levels were elevated, demonstrating that de novo methylation and active demethylation accompanies this transition process. Finally, mutations of IDH1 (IDH1 (R132)) and IDH2 (IDH2 (R172)) leading to production of the TET inhibiting oncometabolite 2-hydroxyglutarate in germ cell cancer cell lines were not detected.

Bats host major mammalian paramyxoviruses.

The large virus family Paramyxoviridae includes some of the most significant human and livestock viruses, such as measles-, distemper-, mumps-, parainfluenza-, Newcastle disease-, respiratory syncytial virus and metapneumoviruses. Here we identify an estimated 66 new paramyxoviruses in a worldwide sample of 119 bat and rodent species (9,278 individuals). Major discoveries include evidence of an origin of Hendra- and Nipah virus in Africa, identification of a bat virus conspecific with the human mumps virus, detection of close relatives of respiratory syncytial virus, mouse pneumonia- and canine distemper virus in bats, as well as direct evidence of Sendai virus in rodents. Phylogenetic reconstruction of host associations suggests a predominance of host switches from bats to other mammals and birds. Hypothesis tests in a maximum likelihood framework permit the phylogenetic placement of bats as tentative hosts at ancestral nodes to both the major Paramyxoviridae subfamilies (Paramyxovirinae and Pneumovirinae). Future attempts to predict the emergence of novel paramyxoviruses in humans and livestock will have to rely fundamentally on these data.

Web-based database for the management of tissue specimens in a transregional histological research facility.

BACKGROUND: In the setting of a histological research core facility sample tracking and project specific archiving of tissue specimens and communication of related data is of central importance. DESCRIPTION: Over a 24-month period 10 laboratories from two transregional research centers submitted in excess of 3000 tissue samples for histological processing and evaluation to our core facility. A web based database was set up to overcome the logistical problem of managing samples with inconsistent, duplicate and missing labels and to allow for efficient sample tracking, archiving and communication with the collaborating research laboratories. The database allows the users to remotely generate unique sample identifiers and enter sample annotation prior to sample processing. Furthermore the database facilitates communication about experimental set-up results and media files such as histological images. CONCLUSION: Our newly constructed web based portal is an important tool for the management of research samples of our histological core facility and facilitates significantly interdisciplinary and transregional research. It is freely available for scientific use.

An acardiac twin with advanced brain development and a minor form of holoprosencephaly and intracerebral retina-like pigmented tissue: a case report and review of the literature.

The development of an acardiac twin in a monochorionic multiple pregnancy is a rare and severe complication of abnormal placental vascular anastomoses. These malformed fetuses present with a very bizarre morphology and a plethora of different malformations. However, all acardiac twins show either a complete absence or an anlage of the heart. Cerebral development is usually poor. We report, according to our review of the literature, for the first time, a very unusual case of acardius with features of acardius amorphus and acormus (fused head and malformed axial skeleton without macroscopically detectable internal organs) with lobar holoprosencephaly and intracerebral pigmented retina-like tissue.