[A case of mucinous cystic neoplasm of the liver].

We present a case of resected mucinous cystic neoplasm of the liver in a 71-year-old woman admitted to our hospital with epigastric discomfort. Abdominal ultrasonography and computed tomography revealed a multi-locular cystic tumor measuring 35 mm in diameter in segment IV of the liver. Left hepatic lobectomy was performed based on the diagnosis of mucinous cystic neoplasm of the liver; subsequent histology revealed that the tumor was multi-locular, cystic, and lined with a single layer of columnar epithelium with low-grade atypia and was associated with a typical ovarian-like stroma. There was no evidence (imaging or histological) to support communication of the cyst with the intrahepatic bile duct, despite modest bile deposition being observed in the cystic wall. The definitive diagnosis was mucinous cystic neoplasm with low-grade intrahepatic epithelial neoplasia.

Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma.

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors.

[A case of primary retroperitoneal mucinous cystadenocarcinoma].

We encountered a case of primary retroperitoneal mucinous cystadenocarcinoma with ovarian-type stroma, an extremely rare condition. The patient was a 56-year-old woman with complaints of diarrhea, nausea, and abdominal fullness. Abdominal ultrasound revealed a nodular multi-cystic mass in the left lower quadrant of the abdomen. Subsequent contrast-enhanced CT and MRI determined it to be of retroperitoneal origin, consistent with a mucinous cystadenocarcinoma. Numerous small nodules were confirmed during the operation around the tumor suggesting local dissemination of the cancer and a left partial colectomy that included these nodules was performed. On histological examination, mucinous fluid was found trapped inside the cavity and poorly differentiated adenocarcinoma was observed in the solid portions. The ovarian-type stroma was confirmed in the layer beneath the epithelial lining and eventually a final diagnosis of mucinous cystadenocarcinoma was reached.

A case of transfusion-transmitted hepatitis E caused by blood from a donor infected with hepatitis E virus via zoonotic food-borne route.

BACKGROUND: Five cases of transfusion transmission of hepatitis E virus (HEV) have been reported so far. The infection routes of the causative donors remain unclear, however. Also, the progress of virus markers in the entire course of HEV infection has not been well documented. STUDY DESIGN AND METHODS: Nucleic acid testing was performed by real-time reverse transcription-polymerase chain reaction targeting the open reading frame 2 region of HEV. Full-length nucleotide sequences of HEV RNA were detected by direct sequencing. RESULTS: Lookback study of a HEV-positive donor revealed that the platelets (PLTs) donated from him 2 weeks previously contained HEV RNA and were transfused to a patient. Thirteen relatives including the donor were ascertained to enjoy grilled pork meats together in a barbecue restaurant 23 days before the donation. Thereafter, his father died of fulminant hepatitis E and the other 6 members showed serum markers of HEV infection. In the recipient, HEV was detected in serum on Day 22 and reached the peak of 7.2 log copies per mL on Day 44 followed by the steep increase of alanine aminotransferase. Immunoglobulin G anti-HEV emerged on Day 67; subsequently, hepatitis was resolved. HEV RNA sequences from the donor and recipient were an identical, Japan-indigenous strain of genotype 4. HEV RNA was detectable up to Day 97 in serum, Day 85 in feces, and Day 71 in saliva. CONCLUSION: A transfusion-transmitted hepatitis E case by blood from a donor infected via the zoonotic food-borne route and the progress of HEV markers in the entire course are demonstrated. Further studies are needed to clarify the epidemiology and the transfusion-related risks for HEV even in industrialized countries.

Recurrence of primary hepatic carcinoid tumor in the remnant liver 13 yr after resection.

We report here a case of primary hepatic carcinoid tumor (PHCT) recurring in the remnant liver 13 yr and 10 mo after first resection. A 70-yr-old man developed four hypervascular tumors in the liver in December 2003. He had undergone curative left-lobe hepatectomy for PHCT in February 1990. Histopathological examination of the tumor biopsy specimen showed that the tumor was composed of uniform round-to-oval cells with solid arrangement and the tumor cells stained positive for chromogranin A, synaptophysin, and neuron-specific enolase. We diagnosed this case as an intrahepatic metastasis of PHCT with a long latency period, based on the fact that no primary site of carcinoid tumor could be found despite intensive examination and the immunohistochemical findings of the resected tumors were essentially same as those of PHCT in 1990. Although PHCT is reported to have a more favorable prognosis than other hepatic cancer or metastatic carcinoid tumor in the liver, long-term observation is recommended.

Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors.

Ewing family tumors (EFTs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor. Although previous reports suggested that these chimeric proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that the LAMB3 gene encoding the beta3 chain of basement membrane protein laminin-5 is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Additionally through use of an antisense oligonucleotide for EWS-ERG in the W-ES EFT cell line, laminin beta3 protein was reduced coordinately with EWS-ERG fusion protein expression. Furthermore, we found small mRNAs were preferentially transcribed from the LAMB3 gene in EFT cell lines. Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells. We show that the small isoforms conferred increased anchorage-independent proliferation to NIH3T3 cells. Together with previous studies showing that laminin-5 is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulation of LAMB3 expression.

Optimal scan timing for coronal enhancement of hypervascular hepatocellular carcinomas and correlation with tumor size: evaluation with four-phase CT hepatic arteriography.

PURPOSE: Our aim was to evaluate coronal enhancement of hypervascular hepatocellular carcinomas (HCCs) on four-phase CT hepatic arteriography (CTHA). MATERIALS AND METHODS: This study included a total of 86 hypervascular HCCs. Four-phase CTHA images were acquired at 10 sec, 35 sec, 60 sec, and 85 sec after the initiation of contrast medium injection. The rate of coronal enhancement on each phase of CTHA of HCCs was analyzed. The rate of coronal enhancement on each phase of CTHA of HCC was also compared with nodule size. RESULTS: All HCCs showed tumor enhancement on phase-one CTHA. The appearance rates of coronal enhancement on phases-two, -three, and -four CTHA were 87.2%, 67.4%, and 53.4%, respectively. The appearance rates of coronal enhancement of small HCCs on phases-two, -three, and -four CTHA were 91.1%, 53.6%, and 30.5%, respectively; those of non-small HCCs were 80.0%, 93.3%, and 96.7%, respectively. On phase-two CTHA, the presence of coronal enhancement was higher in small HCCs than in non-small HCCs. On phases-three and -four CTHA, the presence of coronal enhancement was significantly higher in non-small HCCs than in small HCCs. CONCLUSION: The optimal phase for achieving coronal enhancement depended on tumor size.

Endovascular stent placement for isolated spontaneous dissection of the superior mesenteric artery: report of a case.

Spontaneous dissection of the superior mesenteric artery (SMA) is rare and has been reported only sporadically. The therapeutic options are either a surgical approach, which is the most frequently adopted, or simple observation. We present a patient with acute abdominal pain due to superior mesenteric artery dissection who was successfully treated by percutaneous endovascular stent placement.

Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2.

The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ<-->BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation.

Induction of tenascin-C by tumor-specific EWS-ETS fusion genes.

Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (PNETs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor (most commonly FLI1 or ERG). Although previous reports suggested that these chimera proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that Tenascin-C (TNC) is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Furthermore, through use of an antisense cDNA expression vector we show that expression of endogenous TNC mRNA and protein were reduced coordinately with attenuation of EWS-FLI1 fusion protein expression. A chromatin immunoprecipitation assay showed direct interaction between the TNC promoter and the EWS-FLI1 fusion protein in vivo. In addition, a luciferase reporter assay revealed that EWS-ETSs upregulated the TNC gene through four ETS binding sites in the TNC promoter. High levels of TNC expression were observed in a subset of ES cell lines (3 of 6) and primary tumors (4 of 6). Together with previous studies showing that TNC expression is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulating of TNC expression.

The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors.

We report here that the Id2 (inhibitor of DNA binding 2) gene is a novel target of transcriptional activation by EWS-FLI1 and EWS-ERG, two fusion proteins that characterize Ewing family tumors (EFTs). To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line by retroviral transduction. cDNA microarray analysis revealed that Id2 expression was up-regulated by introducing the EWS-ETS fusion gene but not by the normal full-length ETS gene. An Id2 promoter-luciferase reporter assay showed that transactivation by EWS-ETS involves the minimal Id2 promoter and may function in cooperation with c-Myc within the full-length regulatory region. A chromatin immunoprecipitation assay revealed direct interaction between the Id2 promoter and EWS-FLI1 fusion protein in vivo. Significantly higher expression of Id2 and c-Myc was observed in all of the six EFT cell lines examined compared to six other sarcoma cell lines. Moreover, high levels of Id2 expression were also observed in five of the six primary tumors examined. Id2 is generally thought to affect the balance between cell differentiation and proliferation in development and is highly expressed in several cancer types. Considering these previous studies, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by up-regulating Id2 expression. doi:10.1038/sj.onc.1206025

A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression.

The rat glial progenitor cell line CG-4 can be induced to differentiate into either oligodendrocytes or type-2 astrocytes. In order to identify genes whose expression varies coincident with such phenotypic differentiation, we employed representational difference analysis (RDA) of mRNA. Here, we report 38 cDNAs induced in type-2 astrocytes, oligodendrocytes, or both differentiated states. Among these were known transcription factors, membrane receptors, extracellular matrix proteins, secreted signaling modulators, chromatin regulators and myelin sheath components. In addition several novel genes were identified; among these was a gene induced during the very early stages of astrocyte differentiation that we have named Ieda (induced early in differentiating astrocytes). Several Ieda transcripts were detected by RT-PCR, and appeared to be produced by alternative splicing and promoter usage. The protein deduced from the longest Ieda mRNA exhibited sequence features characteristic of G-protein coupled receptors, including seven putative transmembrane domains, while the shorter Ieda transcripts encoded proteins that lacked several transmembrane segments. In the adult rat, Ieda transcripts were found exclusively in brain and testis. In the developing rat brain, Ieda expression was first detected at embryonic day 16, that is two days before the first appearance of mature astrocytes. Thus, this approach has yielded a potential source of markers for differentiation states of these two cellular types as well as genes predicted to be functionally involved in the differentiation process itself.