Advanced moderately differentiated neuroendocrine carcinoma of the rectum with favorable prognosis by postoperative chemoradiation.

Rectal neuroendocrine carcinoma is rare with poor prognosis. We report herein a case of advanced moderately differentiated neuroendocrine carcinoma of the rectum with relatively favorable prognosis treated by postoperative adjuvant chemoradiation therapy. A 58-year-old Japanese female was referred and colonofiberscopy revealed an easy-bleeding irregular tumor in the lower rectum, which was pathologically diagnosed as a neuroendocrine carcinoma. Surgical treatment consisted of abdominoperineal resection and lymph node dissection. The tumor invaded deeply into perirectal tissues, and 9 of 11 lymph node metastases were observed. Immunohistochemically, chromogranin A showed diffuse and strong staining, and the MIB-1 labeling index was 18.3 +/- 5.6, supporting the high proliferation of the tumor. Some nucleus of the tumor showed positive staining for p21/WAF1. A total dose of 46 Gy of radiotherapy was delivered with 800 mg of daily oral doxifluridine. At 5 years post-surgery, the patient demonstrated no clinical evidence of intrapelvic recurrence or distant metastases.

Neuroendocrine differentiation in stage D2 prostate cancers.

OBJECTIVES: Chromogranin A (CgA) and neuro-specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D(2) prostate cancer patients. METHODS: Immunohistochemistry was carried out using antibodies against CgA and NSE in 58 patients and, pretreatment serum CgA and NSE levels were measured by monoclonal immunoradiometric assay in 18 patients with stage D(2) prostate cancer treated by androgen ablation. We examined the relationship of the pretreatment serum level to IHC findings for CgA and NSE in prostate cancer patients to clinicopathological parameters, and prognosis. Also, we evaluated the correlation of IHC findings to serum levels for CgA and NSE. RESULTS: There was a statistically significant correlation between CgA positivity and serum CgA level (P = 0.0421). However, there was no statistically significant correlation between NSE positivity and serum NSE level (P > 0.05). We divided stage D(2) patients into three groups according to IHC positivity of CgA and NSE. The cause-specific survival was significantly poorer in patients with strongly positive (++) patients for independent CgA and combined CgA with NSE (P = 0.0379). Multivariate analysis of cause-specific survivals in patients with stage D(2) prostate cancer demonstrated that strong IHC stain was considered as independent variable associated with greater risk of death (P = 0.0142). CONCLUSION: Neuroendocrine differentiation in stage D(2) prostate cancer has attracted considerable attention as a potentially findings prognosis. Thus, CgA had a stronger relationship between serum levels and IHC positivity in contrast to NSE, suggesting clinical usefulness as a tumor marker in predicting the extent of neuroendocrine differentiation in prostate cancer.

Serum p53 antibody as a diagnostic marker of high-risk endometrial cancer.

OBJECTIVE: The purpose of this study was to investigate the diagnostic impact of preoperative serum p53 antibody (S-p53 Ab) in patients with endometrial cancer. STUDY DESIGN: A hospital-based series of 67 patients, comprising 58 endometrioid adenocarcinomas (EA) and 9 serous adenocarcinomas (SA) between 1998-2002 were included. First, preoperative pathology was compared with final pathology in terms of histologic classification and tumor grade. Second, S-p53 Ab and CA125 were measured using preoperative serum samples, and immunohistochemical staining for p53 protein was assessed using hysterectomy specimens. RESULTS: There were discrepancies between preoperative and final pathology in terms of histologic classification (7%) and tumor grade in EAs (30%); other objective tests, therefore, were needed to minimize the diagnostic problems. S-p53 Ab titers varied from 0.27-786 (mean, 124) in SAs and from 0.1-7.47 (mean, 0.46) U/mL in EAs, respectively, and were positive in 6 (67%) SAs and in 3 (6%) EAs using 1.3 U/mL as cut-off. S-p53 Ab-positive rate was significantly correlated with SA histology and grade 3 EA tumor (odds ratio, 40; P = .005; 95% confidence interval, 3.04-525.43) with higher sensitivity and higher specificity than p53 staining and CA125, respectively. CONCLUSION: S-p53 Ab could conveniently and specifically identify high-risk endometrial cancer.

Primary diffuse leptomeningeal gliomatosis followed with serial magnetic resonance images.

We report a case of primary diffuse leptomeningeal gliomatosis (PDLG) followed up with serial magnetic resonance images (MRI). A 45-year-old man manifested with bilateral abducens nerve palsy and meningisms. Repeated MRI revealed diffuse leptomeningeal enhancement throughout the central nervous system without intra-axial mass accompanied with the dilatation of ventricles and focally enlarged cerebral sulci. Brain biopsies showed a leptomeningeal gliomatosis. The MRI findings described here would contribute to the diagnosis of PDLG among other common diseases diffusely spreading along the leptomeningeal structures.

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis.

Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF-C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF-C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3-kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF-C and VEGF-A expression in B13LM cells, a lymphatic metastasis-prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF-C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF-A expression was inhibited by all four of these inhibitors. The serum starvation-induced expression of VEGF-C was inhibited by rapamycin, whereas that of VEGF-A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin-treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF-C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis.

Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer.

BACKGROUND: There are therapeutic dilemmas regarding conservative management of endometrial cancer in young women. METHODS: We planned a prospective study to conservatively treat women aged under 40 years with clinical stage 1A, grade 1 endometrioid adenocarcinoma from 1999 to 2005. There were nine women (aged 28-40) who fulfilled the criteria, and medroxyprogesterone acetate (400 mg/day) was continued for 6 months. Curettage materials were pathologically evaluated according to our criteria including partial response (PR) (a small amount of cancer tissue with remarkable hormonal effects or atypical hyperplasia). To predict complete response (CR) to progestin, immunohistochemical staining for insulin-like growth factor type 1 receptor, phosphatase and tensin homolog deleted on chromosome ten, progesterone receptor (PgR), estrogen receptor and Ki67 were assessed. RESULTS: Seven (78%) and two cases presented complete and PRs, respectively. Two patients developed recurrent disease 10 and 22 months after the last dilatation and curettage, and both had synchronous ovarian cancer. However, all nine patients were alive and disease-free for a mean of 39 months. Of eight married patients, four (50%) conceived and three delivered full-term singletons. CR was related to positive expression of PgR (P=0.008). CONCLUSIONS: Patients with an initial PR can obtain CR after further treatment, and the PgR may be useful in predicting CR to fertility-preserving treatment in young women with endometrial cancer.

Angiosarcoma in the right atria demonstrated by fusion images of multislice computed tomography and positron emission tomography using F-18 Fluoro-Deoxyglucose.

Primary cardiac tumors are rare. In this report, using fusion images of multislice computed tomography (MSCT) and positron emission tomography (PET) using F-18 Fluoro-Deoxyglucose, we could diagnose, morphologically, the location, size and extent of the tumor, and degree of blood flow from the feeding artery (by MSCT) and establish that this cardiac tumor was malignant (by PET) before surgical operation. Histologically, the tumor was diagnosed as a cardiac angiosarcoma.

Primary synovial sarcoma in fallopian tube: case report and literature review.

Synovial sarcoma, a malignant mesenchymal neoplasm, occurs mostly near the joints of the extremities and occasionally outside the joint such as lung. We report a case of soft tissue sarcoma arising in the fallopian tube origin that showed characteristic pathological appearance of biphasic synovial sarcoma. Molecular analysis detected a fusion gene transcript of synovial sarcoma translocation (SYT) gene from chromosome 18 and synovial sarcoma X chromosome breakpoint 1 (SSX1) gene, which is believed to pathognomonic for synovial sarcoma of joint origin. Recurrent abdominal tumor, observed at 12 month after the initial surgery and following chemotherapy using doxorubicin, cisplatin and ifosfamide, partially responded to chemotherapy using paclitaxel and carboplatin and, then, optimal surgery was performed. This is the first report of a synovial sarcoma arising in the fallopian tube.

Expression of liver-enriched nuclear factors and their isoforms in alpha-fetoprotein-producing gastric carcinoma cells.

Alpha-fetoprotein (AFP)-producing gastric cancer (AFP-GC) is a highly malignant variant of adenocarcinoma with aberrant hepatocellular phenotype. A detailed understanding of the regulation of its liver phenotype is lacking. Liver-enriched nuclear factors (LENFs) are implicated in the transcriptional regulation of AFP in the fetal liver. To investigate the regulatory role of LENFs in AFP-GCs, the expression of LENFs including CCAAT/enhancer binding protein (C/EBP)-beta, C/EBP-alpha, hepatocyte nuclear factor (HNF)-1alpha, HNF-1beta and HNF-4alpha was investigated in 3 cell lines of AFP-GC and 7 cell lines of control GC. The liver activating protein (LAP), an activating isoform of C/EBP-beta, was predominantly expressed in AFP-GCs, whereas the liver inhibitory protein (LIP), an inhibitory isoform of C/EBP-beta, predominated in the control GCs. HNF-1alpha was relatively suppressed in AFP-GCs. HNF-4alpha was expressed in one of three AFP-GC cell lines. C/EBP-alpha and HNF-1beta were expressed at the same levels in both cell types of GC. AFP-GCs expressed a set of hepatocyte-related proteins (e.g., transferrin and albumin) while they still retained the several glandular cell-related proteins (e.g., MUC2). The induction of LIP reduced transferrin expression and induced CEA expression in an AFP-GC line. Collecting these results, it was suggested that the contribution of LENFs, especially isoforms of C/EBP-beta, is possibly important in phenotypic regulation of AFP-GCs.

Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas.

Gastrointestinal neuroendocrine carcinomas (NECs) are extremely aggressive and poorly prognostic. We showed previously that human achaete-scute homologue gene 1 (hASH1), a basic helix-loop-helix transcription factor regulated by Notch, was aberrantly expressed in NECs. To date, no effective therapeutic strategies for NECs have been investigated. Notch, Wnt and Hedgehog (Hh) signalings are important for stem cell self-renewal and carcinogenesis in the gastrointestinal epithelium. In this study, we showed that Hh signaling was clearly upregulated in NECs in Gli1-dependent manner. Specific therapeutic effects of cyclopamine on NECs were also demonstrated. RT-PCR showed that among eight frozen samples (three NECs, one carcinoid tumor, three adenocarcinomas and one normal mucosa), the band intensities of Gli1 were the strongest in NECs, moderately strong in a carcinoid tumor, very weak in adenocarcinomas and undetectable in a normal mucosa. In real-time RT-PCR, the expression levels of Gli1 in NECs were 108.4, 28.6 and 16.3 times higher than that in an adenocarcinoma. In immunohistochemistry using 25 paraffin-embedded tissues, all twelve NECs and three of six carcinoid tumors showed positive stainings for Gli1, whereas six of seven adenocarcinomas were negative. In vitro, RT-PCR showed that NEC cell lines expressed Gli1 mRNA significantly. Administration of cyclopamine suppressed cell proliferation and invasion, and induced apoptosis in NECs. In cyclopamine-treated NECs, downregulation of Gli1, Ptch1, Snail and hASH1, and upregulation of E-cadherin were demonstrated at mRNA levels. Such effects were not observed in a Gli1-negative colonic adenocarcinoma cell line or in control alkaloid-treated NECs. Hh signaling may play a crucial role in the pathophysiology of NECs. Blockade of Hh pathway using cyclopamine or its synthetic derivatives might open an effective therapeutic strategy to NECs, not only by suppressing tumor viability but also by altering tumor cell nature.

The effects of carbon ion irradiation revealed by excised perforated intestines as a late morbidity for uterine cancer treatment.

PURPOSE: Clinical trials of carbon ion therapy have been performed due to the advantages of high-dose energy delivery with precise localization control to targeted organs and strong cell-killing activities to cancers. Perforated intestines as a late morbidity after carbon ion radiotherapy for uterine cancers were examined to reveal the biological characteristics of carbon ion for future applications for the treatment of gastrointestinal cancers. METHODS: Between June 1995 and December 2004, 94 patients with carcinoma of the uterine cervix or corpus were treated with carbon ion therapy. Among them, 9 patients (9.6%) developed major late gastrointestinal (GI) complications. Four out of 9 patients had intestinal perforations excised operatively at our institute. The postoperative clinical courses and histopathological findings of the excised intestine were investigated. RESULTS: Carbon ion irradiation severely damaged smooth muscle layers by coagulation necrosis as well as atrophy of the intestinal epithelium and middle-sized arterial thromboses of the intestines. After evaluating late complications, the dose constraints on the GI tracts were set under 60 GyE to prevent major complications. Thereafter, the incidence of major GI complications markedly decreased. CONCLUSION: Our findings demonstrated the characteristic histopathological effects of carbon ion radiotherapy and thus are expected to facilitate future additional applications of carbon ion radiotherapy for the treatment of gastrointestinal cancers.

Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines.

Pancreatic cancer still remains a serious health problem with <5% 5-year survival rate for all stages. To develop an effective treatment, it is necessary to identify a target molecule that is crucially involved in pancreatic tumor growth. We previously observed that Pim-3, a member of the proto-oncogene Pim family that expresses serine/threonine kinase activity, was aberrantly expressed in human and mouse hepatomas but not in normal liver. Here, we show that Pim-3 is also expressed in malignant lesions of the pancreas but not in normal pancreatic tissue. Moreover, Pim-3 mRNA and protein were constitutively expressed in all human pancreatic cancer cell lines that we examined and colocalized with the proapoptotic protein Bad. The ablation of endogenous Pim-3 by small hairpin RNA transfection promoted apoptosis, as evidenced by increases in a proportion of cells in the sub-G(1) fraction of the cell cycle and in phosphatidyl serine externalization. A proapoptotic molecule, Bad, was phosphorylated constitutively at Ser(112) but not Ser(136) in human pancreatic cancer cell lines and this phosphorylation is presumed to represent its inactive form. Phosphorylation of Bad and the expression of an antiapoptotic molecule, Bcl-X(L), were reduced by the ablation of endogenous Pim-3. Thus, we provide the first evidence that Pim-3 can inactivate Bad and maintain the expression of Bcl-X(L) and thus prevent apoptosis of human pancreatic cancer cells. This may contribute to the net increase in tumor volume or tumor growth in pancreatic cancer.

Assessment of rectal aberrant crypt foci by standard chromoscopy and its predictive value for colonic advanced neoplasms.

BACKGROUND AND AIMS: Aberrant crypt foci (ACF) are thought to be preneoplastic lesions and are assessed by magnifying chromoscopy with methylene blue staining. The aim of this study was to evaluate the predictive value of rectal ACF recognized by conventional chromoscopy for colonic advanced neoplasms. METHODS: Total colonoscopy, involving rectal chromoscopy using indigo carmine with standard colonoscopies, was performed on 386 patients. Patients who showed no ACF were classified as Grade 0, and those who had 1-4, 5-9, and 10+ ACF were classified as Grades 1, 2, or 3, respectively. The correlation between ACF grading and the prevalence of colonic advanced neoplasm, any adenoma>or=1 cm in size and/or with villous or tubulovillous morphology, and/or with high-grade dysplasia or invasive cancer, was assessed. RESULTS: Sixty-three patients were classified as ACF Grade 0, 119 as Grade 1, 116 as Grade 2, and 88 as Grade 3. Colonic advanced neoplasm was observed in 4 patients (6.3%) for Grade 0, 43 (36.1%) for Grade 1, 61 (52.6%) for Grade 2, and 57 (64.8%) for Grade 3. As the ACF grade increased, the chance of a patient having a colonic advanced neoplasm increased. For multivariate analyses, compared with patients with Grade 0, those with Grades 1, 2, or 3 had a greater risk of colonic advanced neoplasm (odds ratio [OR] 9.18, 95% CI 3.08-27.33, OR 20.44, 95% CI 6.81-61.42, and OR 32.94, 95% CI 10.49-103.41, respectively). CONCLUSIONS: Chromoscopic assessment of rectal ACF by conventional techniques is useful for predicting colonic advanced neoplasms.

Activation of genes for growth factor and cytokine pathways late in chondrogenic differentiation of ATDC5 cells.

The mouse embryonal carcinoma cell line ATDC5 provides an excellent model system for chondrogenesis in vitro. To understand better the molecular mechanisms of endochondral bone formation, we investigated gene expression profiles during the differentiation course of ATDC5 cells, using an in-house microarray harboring full-length-enriched cDNAs. For 28 days following chondrogenic induction, 507 genes were up- or down-regulated at least 1.5-fold. These genes were classified into five clusters based on their expression patterns. Genes for growth factor and cytokine pathways were significantly enriched in the cluster characterized by increases in expression during late stages of chondrocyte differentiation. mRNAs for decorin and osteoglycin, which have been shown to bind to transforming growth factors-beta and bone morphogenetic proteins, respectively, were found in this cluster and were detected in hypertrophic chondrocytes of developing mouse bones by in situ hybridization analysis. Taken together with assigned functions of individual genes in the cluster, interdigitated interaction between a number of intercellular signaling molecules is likely to take place in the late chondrogenic stage for autocrine and paracrine regulation among chondrocytes, as well as for chemoattraction and stimulation of progenitor cells of other lineages.

Dexamethasone modifies the susceptibility to serum cytotoxicity and increases the metastatic efficiency of a colon carcinoma cell line.

Metastatic inefficiency is a phenomenon by which a majority of tumor cells is lost in the blood stream during the metastatic process. We investigated the effects of dexamethasone (DEX), a synthesized glucocorticoid, on the serum susceptibility of a colon carcinoma cell line, HT-29, with respect to metastatic inefficiency. The susceptibility to serum cytotoxicity of these carcinoma cells is possibly an important factor in metastatic inefficiency. In this study, we used glucocorticoid because it modifies the function of the plasma membrane and has been shown to enhance the hematogenous metastasis of some tumor cells. Using HT-29 cells that had been treated with DEX in vitro, the following factors were evaluated: the metastasis of intrasplenic injected cells; in vitro and in vivo proliferation; motility; the production of matrix metalloproteinases (MMPs); and the expression of the membrane complement regulatory proteins CD46, CD55, and CD59. The number of viable cells in the liver after an intraportal injection of tumor cells was determined by the expression of human beta-globin mRNA that is aberrantly expressed in HT-29 cells. In addition, we investigated 100% serum-induced proliferation, susceptibility, and apoptosis. Treatment with DEX was found to accelerate liver metastasis; here, the number of metastatic colonies and the weight of the liver were both significantly increased in DEX-treated HT-29 (HT-29DEX) cells. In contrast, there was no difference in terms of cell motility; the production of MMPs; or the expression of CD46, CD55, or CD59 between the HT-29 and HT-29DEX cells. The HT-29DEX cells exhibited enhanced proliferation in the serum, as well as resistance to cytotoxicity when exposed to 100% serum. In addition, DEX slightly inhibited serum-induced apoptosis. Finally, the expression of colon cancer-derived beta-globin mRNA was detectable 24 h after intravenous injection, but only in samples obtained from the HT-29DEX-, but not in those from the HT-29-inoculated mice. These results indicate that DEX reduced the metastatic inefficiency of the HT-29 cells, resulting in a hematogenous metastasis-prone phenotype. It is thus expected that the acquisition of resistance against serum cytotoxicity is among the mechanisms that contribute to the efficiency of hematogeneous metastasis.

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia.

BACKGROUND: Maternal viral infection is associated with increased risk for schizophrenia. It is hypothesized that the maternal immune response to viruses may influence fetal brain development and lead to schizophrenia. METHODS: To mimic a viral infection, the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was administered into pregnant mice. Behavioral evaluations (thigmotaxis, methamphetamine [MAP]-induced hyperactivity, novel-object recognition test [NORT]), sensorimotor gating (prepulse inhibition [PPI]), and biochemical evaluation of the dopaminergic function of the offspring of phosphate-buffered saline (PBS)-treated dams (PBS-mice) and that of poly I:C-treated dams (poly I:C-mice) were examined. RESULTS: In juveniles, no difference was found between the poly I:C-mice and PBS-mice. However, in adults, the poly I:C-mice exhibited attenuated thigmotaxis, greater response in MAP-induced (2 mg/kg) hyperlocomotion, deficits in PPI, and cognitive impairment in NORT compared with the PBS-mice. Cognitive impairment in the adult poly I:C-mice could be improved by subchronic administration of clozapine (5.0 mg/kg) but not haloperidol (.1 mg/kg). Increased dopamine (DA) turnover and decreased receptor binding of D2-like receptors, but not D1-like receptors, in the striatum were found in adult poly I:C-mice. CONCLUSIONS: Prenatal poly I:C administration causes maturation-dependent increased subcortical DA function and cognitive impairment in the offspring, indicating a neurodevelopmental animal model of schizophrenia.

A pilot approach for quantitative assessment of liver fibrosis using ultrasound: preliminary results in 79 cases.

BACKGROUND/AIMS: Ultrasound is noninvasive and useful to evaluate liver disease despite its operator dependency. This pilot study was conducted to quantitatively assess liver fibrosis using ultrasound. METHODS: Fibrosis extraction ratios (FER) (fiber volume/total volume) of ultrasound and histological images of 8 autopsy specimens were compared. We also compared FER of ultrasound images from clinical patients (n=79) with histological fibrosis stages. RESULTS: In the autopsy study, FER correlation coefficient between histological images and ultrasound images was 0.992. Regarding clinical patients, there was sufficient evidence to indicate differences in the distributions of FER for each fibrosis stage (Kruskal-Wallis test P<0.0001). With FER cut-off to distinguish > or =F2 from F0 and F1 defined as mean plus standard deviation of F0 and F1, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio were 62, 75, 78, 57%, and 2.47, respectively. Regarding HCV cohort (n=44), they were 55, 87, 89, 50%, and 4.14, respectively. Areas under receiver operating characteristic curves were 0.78, 0.79, 0.83 and 0.83 for > or =F1, > or =F2, > or =F3 and =F4, respectively. Regarding HCV cohort, they were 0.74, 0.71, 0.79 for > or =F2, > or =3 and =4, respectively. CONCLUSIONS: The FER method has great potential for diagnosing liver fibrosis using ultrasound.

Regulatory role of hepatocyte nuclear factor-4alpha on gastric choriocarcinoma function.

Gastric choriocarcinoma is a highly aggressive carcinoma, most probably originating from somatic cells in the gastric mucosal layer. We herein investigated the regulatory role of hepatocyte nuclear factor (HNF)-4alpha, a transcriptional regulator expressed in non-neoplastic and neoplastic gastric tissues, on functions of gastric choriocarcinoma cells. HNF-4alpha cDNA was stably transfected to a gastric choriocarcinoma cell line, SCH. Alterations in SCH cell functions such as histology, ultrastructure, proliferation, production of trophoblast-specific proteins, and chemosensitivity to methotrexate (MTX) were examined. Neither in vitro and in vivo proliferations nor HLA-G expression differed significantly between the mock-transfected and HNF-4alpha-transfected SCH cells, while suppressed human chorionic gonadotropin (hCG) secretions, increased human placental lactogen (hPL) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) immunoreactivity, and decreased chemosensitivity to MTX were seen in HNF-4alpha-transfected SCH cells. General histologic features in xenograft nodules were unaltered, but, ultrastructurally, fascicles of paranuclear filaments were significantly more numerous in HNF-4alpha-transfected SCH cells. These results indicated an HNF-4alpha-rendered functional regulation in SCH cells, suggesting a role of transcriptional factors abundant in gastric but not in trophoblastic tissues/cells on the functional modulation of gastric choriocarcinoma cells.

The expression of hepatocyte nuclear factor-4alpha, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas.

AIMS: Hepatocyte nuclear factor (HNF)-4alpha is a developmental regulator of the visceral endoderm, which is expressed in the embryonic gut and later in the adult intestine and colon. However, adult gastric mucosa does not express HNF-4alpha. We investigated the possible involvement of HNF-4alpha in intestinal metaplasia and the intestinalisation of gastric adenocarcinomas. METHODS: Thirty-five cases of adenocarcinomas and 46 cases of adjacent non-neoplastic mucosa with (22 lesions) or without (24 lesions) intestinal metaplasia were immunostained for HNF-4alpha. The gastric or the intestinal phenotype was also examined using immunohistochemistry for MUC5AC, MUC2, CD10, and gastric-type mucin (GTM). Adenocarcinomas were classified into the gastric type (G-type, 42.9%), the mixed gastric and intestinal type (GI-type, 31.4%), and the intestinal type (I-type, 25.7%). RESULTS: The HNF-4alpha expression was exclusively seen in glandular cells with intestinal metaplasia, which was correlated with MUC2 expression (p<0.05) and inversely correlated with MUC5AC expression (p<0.05). All adenocarcinomas more or less expressed HNF-4alpha, with an intense expression being seen in the I-type (p<0.01) and in well-differentiated adenocarcinomas (p<0.03). CONCLUSIONS: HNF-4alpha expression is associated with the intestinal phenotype of non-neoplastic and neoplastic gastric glandular cells, suggesting a possible involvement in the establishment and/or maintenance of the intestinal phenotype of the gastric mucosa and adenocarcinomas.