Yoshiharu Ohaki

Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas.

Cell growth can be induced via elicitation of protease‐activated receptors (PAR) with serine proteases such as thrombin and trypsin.

Helicobacter pylori infection increases the risk of colorectal adenoma and adenocarcinoma, especially in women

BackgroundRecent reports suggest that Helicobacter pylori infection can potentially increase the risk of colorectal cancer. The purpose of this study was to assess the association between H. pylori infection and the risk of colorectal adenoma and adenocarcinoma, and to evaluate any differences on the basis of sex.MethodsThe subjects were 669 (40- to 80-year-old) patients who underwent both barium enema examination and total colonoscopy, and who were evaluated for H. pylori infection by 13C-urea breath test, urease test, or histological diagnosis of biopsied gastric specimens. There were 142 H. pylori-negative and 527-positive patients. The odds ratios (ORs) for H. pylori-positive patients with colorectal adenoma and adenocarcinoma, and for tumor patients with either adenoma or adenocarcinoma were calculated.ResultsAmong the H. pylori-negative patients, there were 52 patients without tumor, 63 with adenoma, 27 with adenocarcinoma, and 90 with tumor. Among the H. pylori-positive patients, there were 136, 264, 127, and 391 patients respectively. Pooling all subjects, those infected with H. pylori had a significantly increased OR for adenoma, adenocarcinoma, or tumor, compared to H. pylori-free patients (OR, 1.60, 1.80, and 1.66, respectively). For female H. pylori-positive subjects, the risk of having adenocarcinoma or tumor was significantly higher than that for their H. pylori-free counterparts, while for male H. pylori-positive and -negative subjects, there was no such significant difference.ConclusionsThe results therefore suggest that, in patients aged 40–80 years, H. pylori infection increased the risk of colorectal adenoma and adenocarcinoma, with significantly higher risks for female patients.

Histological distribution of class III alcohol dehydrogenase in human brain.

The distributions of class III alcohol dehydrogenase (ADH), a glutathione-dependent formaldehyde dehydrogenase, and class I ADH in the human brain were examined immunohistochemically. The most intense immunostaining of class III ADH was observed in the dendrites and cytoplasm of cerebellar Purkinje cells. Scattered cerebral cortical neurons in layers IV and V, and some hippocampal pyramidal neurons were also immunopositive. The neuronal distribution of class III ADH resembled that of the vulnerable neurons in patients with hypoxic encephalopathy, which in view of the intense staining in the Purkinje cells, raises the possibility that this enzyme contributes to the hypoxia and cerebellar degeneration suffered by chronic alcoholics. Perivascular and subependymal astrocytes, which contribute to the maintenance of the cerebral cellular milieu and isolate the brain from the systemic circulation and cerebrospinal fluid, were also class III ADH positive. As the substrates of this enzyme include intrinsic toxic formaldehyde, inflammatory intermediate of 20-hydroxy-leukoteiene B4, and possibly ethanol, the distribution of class III ADH immunostaining indicates this enzyme contributes to the defence of the brain against degenerative processes. The finding that, unlike ependymal cells, subependymal astrocytes were class III ADH positive, suggests this enzyme may be useful for differentiating astrocytes and ependymal cells.

Overexpressed fibroblast growth factor receptor 2 in the invasive front of colorectal cancer: A potential therapeutic target in colorectal cancer

Fibroblast growth factor receptor 2 (FGFR2) is considered a novel therapeutic target for various cancer. We used a silencing strategy to clarify the effect of reduced FGFR2 expression in human colorectal cancer (CRC) cells. The invasive front of cancer cells exhibited stronger FGFR2 expression than the surface area of the cancers. FGFR2 shRNA-transfected LoVo cells inhibited cell migration, invasion and tumor growth in vitro and in vivo. Thus, FGFR2 plays important roles in CRC progression in association with tumor cell migration, invasion and growth, and FGFR2 might be a novel therapeutic target for CRC.

A case report of renal cell tumor in a 45-year-old female mimicking lower portion nephrogenesis

This report describes a renal tumor with an unusual histology In a 45‐year‐old woman. The tumor was white in color, different from usual renal cell carcinoma, and mainly consisted of variously shaped tubules formed by flat or cuboid cells within marked edematous stroma. Elaborated branching or tubules arranged In a papillary pattern with focal spindle‐shaped cell proliferation were characteristic features. Immunohistochemical staining expressed diffusely positive for vlmentin and S‐100 protein, partially positive for cytokeratin and epithelial membrane antigen and negative for Leu‐M1, Leu‐7, CD34 and markers for muscle cells. Ultrastructural studies of the tumor cells showed adenocarcinoma‐IIke characteristics. According to these histological, Immunohistochemlcal and electron microscopy findings, it is suggested that this tumor be designated as unclassified renal cell carcinoma with histology mimicking lower‐nephron nephrogenesis.

Mosaic-like distribution of endothelial cell antigens in capillaries and juxta-alveolar microvessels in the normal human lung

The distribution patterns of endothelial cell antigens, including thrombomodulin and von Willebrand factor (vWf), were studied in normal lung tissues obtained from distant areas of solitary nodules (seven adenocarcinomas and four hamartomas). By single immunoalkaline phosphatase and dual immunofluorescence stainings, the plasma membranes of alveolar capillary endothelium showed linear distribution of thrombomodulin, but their cytoplasm was rarely reactive for vWf (thrombomodulin‐dominant pattern). Microvessels with a diameter larger than 10 μm located in the connective tissue zones demonstrated band‐like reaction for vWf in their cytoplasm, and their plasma membranes often lacked reactivity for thrombomodulin (vWf‐dominant pattern). The juxta‐alveolar microvessels located along the borders between the alveolar‐ and connective‐tissue zones showed mosaic‐like pattern of distribution for these antigens. The pulmonary venules and peribronchial microvessels measuring up to 40 μm in diameter, demonstrated the expression of thrombomodulin along the plasma membrane, and that of vWf in the cytoplasm. Capillaries of the bronchial circulation were also characterized by mosaic‐like pattern of distribution. Both antigens were often expressed in a single cytoplasmic segment. The heterogeneous distribution pattern of these antigens suggests topographic difference in endothelial cell function to maintain coagulatory and anticoagulatory balance in the normal human lung.

Role of cdk4, p16INK4, and Rb Expression in the Prognosis of Bronchioloalveolar Carcinomas

Background: The p16INK4 protein has been identified as a potent inhibitor of cyclin-dependent kinase (cdk)4 by blocking cdk4-mediated phosphorylation of the tumor suppressor retinoblastoma (Rb) protein, thus allowing Rb-mediated growth suppression. Objectives: Loss of p16INK4 has been associated with a poor cancer prognosis, but its potential significance in bronchioloalveolar carcinomas (BACs) has not been explored. Methods: We examined immunohistochemical expression of p16INK4, cdk4, and Rb proteins in 38 BACs and correlated their expression levels with known clinicopathological features of the disease. Results: All BACs expressed cdk4, while 89 and 82% expressed p16INK4 and Rb proteins, respectively. None of the clinicopathological factors correlated with p16INK4, cdk4, or Rb expression separately. A low p16INK4/cdk4 ratio was significantly associated with a high disease stage (p = 0.04), and the ratio tended to be lower in mucinous than nonmucinous tumors. BACs with a low p16INK4/cdk4 ratio showed significantly higher Rb expression levels (p = 0.02). Univariable survival analyses showed a significantly lower 5-year survival probability in patients with a high stage (p = 0.002) or low p16INK4/cdk4 ratio (p = 0.01). Conclusions: The results suggest a role of the cdk4/p16INK4 pathway in the prognosis of BACs. Further studies are warranted to clarify whether a low p16INK4/cdk4 ratio may identify tumors that are destined to behave unfavorably.

A case of ovarian endometrioid adenocarcinoma with yolk sac tumor component in a postmenopausal woman.

The co‐existence of an endometrioid adenocarcinoma with an ovarian yolk sac tumor is very rare. Only eight cases have been reported in the English language literature. A 54‐year‐old postmenopausal woman with a 6‐month history of progressive abdominal distension was seen at our hospital. MR imaging revealed a large cyst with a solid intramural node. Serum α‐fetoprotein and CA125 levels were 13143 ng/ml and 170 U/ml, respectively. At laparotomy, a large tumor approximately 20 cm in diameter was found to occupy the abdominal cavity, adhering to the swollen appendix and part of the omentum. Microscopically, foci of endometrioid adenocarcinoma together with a yolk sac tumor component were observed within a large endometriotic cyst. Since the tumor was clinically staged 1c, the patient was given 500 mg of intraperitoneal carboplatin postoperatively, followed by five courses of combination chemotherapy consisting of cisplatin, etoposide and peplomycin at 4‐week intervals. The levels of both serum α‐fetoprotein and CA 125 decreased gradually to normal ranges and remained normal at the most recent follow‐up on 29 December, 2001. In contrast to a very poor prognosis of this tumor in previously reported cases, our patient showed no sign of recurrence during a 21‐month follow‐up period.

Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar pathology

Abstract A 67-year-old woman had frequent subacute ileus, hearing difficulty, muscle atrophy and stroke-like episodes. Computed tomography revealed multiple low-density areas, which did not correlate with the vascular supply, in the cerebral cortex. She had metabolic disturbance comprising lactic acidosis and elevated pyruvate level. Her skeletal muscle biopsy specimen showed ragged-red fibers, and mitochondrial DNA analysis revealed a point mutation at position 3243, findings consistent with MELAS. Examination of her small intestine revealed a necrotic zone and numerous abnormal large mitochondria in the smooth muscle cells, vascular media and endothelium, and intestinal ganglion cells. The cerebral cortex showed multiple microcystic necrotic foci in cerebral cortex. Cactus-like pathology resembling the changes associated with Menkes’ kinky hair disease and torpedoes were observed in the cerebellar Purkinje cells. The intestinal dysmotility due to MELAS and cerebellar changes were presumed to be associated with a disturbance of copper metabolism.

Epithelioid trophoblastic tumor of the uterus: cytological and immunohistochemical observation of a case.

Epithelioid trophoblastic tumor (ETT) is a new entity of trophoblastic tumor and 14 such cases were reported by Shih and Kurman in 1998. However, only three subsequent cases supporting ETT have been reported. Recently, we experienced a case of ETT in a 37‐year‐old woman whose preoperative endometrial brushings showed atypical mononucleate giant cells and who underwent hysterectomy with the diagnosis of a uterine fibroid. The specimens revealed a 2.5 × 3.0 cm yellow–tan intramural nodule located in the lower uterine segment, which was composed of a neoplastic proliferation of intermediate trophoblasts in epithelioid arrangements. Immunohistochemically, the tumor cells were diffusely positive for cytokeratin and inhibin‐α, and focally positive for human chorionic gonadotropin and human placental lactogen. She presented an uneventful clinical course as of September 2001.