Hiroshi Ishikura

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.

Expression of regulator of G protein signalling protein 5 (RGS5) in the tumour vasculature of human renal cell carcinoma

The gene expression profiles of tumour and normal vasculature are distinctively different. The altered expression of various angiogenesis‐related genes in tumour‐derived endothelial cells has been investigated intensively, but there may be as yet unidentified molecules that regulate tumour angiogenesis. In the present study, the distinctive expression of regulator of G protein signalling protein 5 (RGS5) in tumour vessels in human renal cell carcinoma (RCC) has been clarified. RGS5 is a member of the RGS superfamily and acts as a negative regulator of heterotrimeric G protein‐mediated signalling through G protein‐coupled receptors (GPCRs). RT‐PCR showed strong expression of RGS5 in all RCCs examined, but expression was very weak or undetectable in normal kidneys. By real‐time RT‐PCR, the ratio of RGS5 mRNA in RCC to that in normal kidney was 6.6 : 1 (p = 0.0012). In situ hybridization showed strong expression of RGS5 in vessels within tumour cell nests. It was expressed neither in tumour cells nor in normal renal capillaries. Immunohistochemical staining using serial sections for endothelial cell markers (CD31 and CD34) and smooth muscle cell markers (α‐SMA and desmin), as well as fluorescence double staining, strongly suggested that tumour endothelial cells were the main location of RGS5 in RCC. These findings suggest that RGS5 may be involved in G protein‐mediated signalling in tumour vessels in human RCC. Copyright

Hepatoid carcinoma of the ovary: a report of three cases admixed with a common surface epithelial carcinoma.

&NA; Hepatoid carcinoma of the ovary is an ovarian carcinoma that has phenotypic properties in common with hepatocellular carcinomas. However, the extent of the tumor cells’ similarity to and their difference from hepatocytes is largely unknown. In addition, the precursor cell of origin for hepatoid carcinoma of the ovary has not been identified. Three cases of alpha‐fetoprotein‐producing hepatoid carcinoma of the ovary that were admixed with an adenocarcinoma of common surface epithelial type are reported. The hepatoid carcinomas had a trabecular architecture with canaliculi detected by polyclonal (but not monoclonal) anticarcinoembryonic antigen antibodies. A hepatic phenotype in the hepatoid tumor cells was further supported by the production of albumin mRNA by in situ hybridization. The adenocarcinomas in the three cases were mucinous (Case 1), serous (Case 2), and endometrioid (Case 3), respectively. The cytokeratin (CK) profile in both the hepatoid and adenocarcinomatous components was CK18+/CK19+/CK20±, whereas normal and neoplastic hepatocytes were CK18+/CK19‐/CK20‐. Although this study supports a hepatic phenotype in ovarian hepatoid carcinoma, the CK profile of hepatoid carcinoma differs from that of normal and neoplastic hepatocytes but resembles that of the associated common epithelial adenocarcinoma. These findings suggest that hepatoid carcinoma of the ovary is probably derived from carcinomas of surface epithelial origin by a process of neometaplasia or transdifferentiation.

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 ≥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.

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 D2 prostate cancer patients.

Evidence for hepatocellular differentiation in alpha-fetoprotein-negative gastric adenocarcinoma with hepatoid morphology: a study with in situ hybridisation for albumin mRNA

Aim: Hepatoid adenocarcinoma, a putative chemosensitive tumour, is defined as a tumour with aberrant hepatocellular differentiation occurring in extrahepatic organs such as the stomach, usually in the gastrointestinal tract. Differentiation in the hepatocellular direction is usually supported by the production of α‐fetoprotein (AFP) and, more recently, albumin (ALB) mRNA. We investigated ALB mRNA to address whether adenocarcinoma with hepatoid morphology, regardless of AFP production, can be diagnosed solely by morphological criteria as a hepatoid adenocarcinoma. Methods: We performed in situ hybridisation (ISH) and immunohistochemistry (IH) for ALB mRNA on AFP‐negative gastric adenocarcinomas with hepatoid morphology. AFP‐positive hepatoid adenocarcinomas and AFP‐negative conventional gastric adenocarcinomas were also investigated as positive and negative controls, respectively. Results: All three gastric adenocarcinomas with hepatoid morphology with no evidence of AFP production stained positive for ALB mRNA, thus providing evidence of differentiation in the hepatocellular direction. Three of five cases of AFP‐positive hepatoid adenocarcinoma of the stomach were positive for ALB mRNA, while 11 cases of AFP‐negative conventional gastric adenocarcinoma were negative. Conclusion: The present study demonstrates that, irrespective of AFP production, gastric adenocarcinoma with morphological patterns suggestive of hepatoid differentiation should be diagnosed as hepatoid adenocarcinoma with important prognostic implications.

Vaccination of fusion cells of rat dendritic and carcinoma cells prevents tumor growth in vivo

Several reports on immunotherapy using dendritic cells‐based vaccine have been published. We investigated findings using fusion cells (FCs) generated from rat dendritic cells and a syngeneic hepatic cancer cell line with regard to inducing anti‐tumor immunity. Vaccination of rats using FCs protected against growth of the subcutaneously implanted tumor in vivo and induced infiltration of CD8+ T cells into the tumor. At the site of CD8+ T cell infiltration, there were apoptotic tumor cells. T cells from spleen of FCs‐vaccinated rats with protective ability against tumor growth included tumor specific cytotoxic CD8+ T cells restricted to major histocompatibility complex Class I. In addition, adaptive transfer of in vitro re‐stimulated splenic T cells with FCs was effective in preventing tumor growth and in vivo vaccinations of rats with FCs after resection of the subcutaneous implanted tumor inhibited local tumor recurrences. Immunotherapy using FCs appears to be an effective method if used in combination with surgical or other anti‐cancer therapies.

Breast cancer incidence and estrogen receptor α in normal mammary tissue—An epidemiologic study among Japanese women in Japan and Hawaii

We have undertaken a study to examine whether the difference in breast cancer incidence between 2 populations of similar genetic background is reflected in a similar pattern of estrogen receptor α expression in normal mammary gland. Study participants were 92 Japanese women from Sapporo, Japan (mean age 48.2 years) and 49 Japanese women from Honolulu, Hawaii (mean age 45.4 years), who underwent biopsy indicating normal breast tissue or benign, nonproliferative breast disease in hospitals in Sapporo, Japan and Honolulu, Hawaii. The breast tissue samples were formalin‐fixed and paraffin‐embedded. The estrogen receptor immunohistochemistry assays were conducted using Dako kits. Japanese women in Hawaii, who have a higher incidence of breast cancer compared with Japanese women in Sapporo, also had, as predicted, higher mean percentage of estrogen receptor α‐positive normal mammary cells (2‐tailed test, p ∼ 0.09). The results of our study are compatible with the hypothesis that estrogen receptor α expression in normal mammary tissue increases breast cancer risk and they also indicate that the expression of these receptors is dependent, at least in part, on nongenetic factors.

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

Aims: Hepatocyte nuclear factor (HNF)‐4&agr; 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‐4&agr;. We investigated the possible involvement of HNF‐4&agr; 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‐4&agr;. 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‐4&agr; 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‐4&agr;, with an intense expression being seen in the I‐type (p<0.01) and in well‐differentiated adenocarcinomas (p<0.03). Conclusions: HNF‐4&agr; 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.

Dumbbell‐shaped leiomyosarcoma of the inferior vena cava with foci of rhabdoid changes and osteoclast‐type giant cells

An inferior vena cava (IVC) tumor was incidentally found in a 67‐year‐old Japanese man. The resected tumor was lobulated and multinodular, measuring 14.0 × 6.5 × 7.0 cm, showing a dumbbell‐shaped appearance with a central constriction. The tumor showed both intra‐ and extra‐luminal growth. The tumor was primarily composed of well‐differentiated leiomyosarcoma. Spindle tumor cells in the well‐differentiated area were positive for vimentin, muscle actin, α‐smooth muscle actin, and desmin. Foci of rhabdoid cells and osteoclast‐type multinucleated giant cells were also found. Rhabdoid cells ultrastructurally had paranuclear aggregates or whorls of intermediate filaments that were positive for vimentin, low molecular weight cytokeratin, and desmin. Osteoclast‐type multinucleated giant cells were positive for only CD68 antigen, suggesting a reactive histiocytic lineage. To the best of our knowledge, this is the first case of IVC leiomyosarcoma accompanied by both rhabdoid tumor cells and osteoclast‐type reactive multinucleated giant cells. These unusual features should be kept in mind in the diagnosis of dumbbell‐shaped retroperitoneal tumors that involve the IVC.