Yoshihiko Ueda

Intraosseous benign notochordal cell tumours: overlooked precursors of classic chordomas?

Aims:  Intraosseous benign notochordal cell tumour is a recently recognized condition that may undergo malignant transformation to classic chordoma. The aim of this study was to describe its clinicopathological characteristics.

Benign notochordal cell tumors: A comparative histological study of benign notochordal cell tumors, classic chordomas, and notochordal vestiges of fetal intervertebral discs

Intraosseous benign notochordal cell tumors are recently recognized conditions that may undergo malignant transformation to classic chordomas. This study attempts to define the morphologic and immunohistochemical characteristics of 34 benign notochordal cell tumors by contrasting them with classic chordomas and the notochordal vestiges in fetal intervertebral discs. Benign notochordal cell tumors were characterized by well-demarcated though unencapsulated sheets of adipocyte-like vacuolated and less vacuolated eosinophilic cells within axial bones. The round nuclei were mildly polymorphic but bland. The tumor cells often contained cytoplasmic eosinophilic hyaline globules and lack any intercellular myxoid matrix or necrosis. The involved bone trabeculae were often sclerotic without evidence of bone destruction. The histologic features were different from those of both notochordal vestiges in fetal intervertebral discs and classic chordomas. There was overlap in immunohistochemical reactivity of benign notochordal cell tumors and chordomas, but notochordal vestiges failed to demonstrate cytokeratin 18 positivity. A more appropriate term for the lesions is “benign notochordal cell tumor” rather than “notochordal rest” or “notochordal hamartoma” as they are not rests and do not fulfill the definition of hamartoma. Benign notochordal cell tumors do not need any surgical procedure and must be adequately recognized to prevent unnecessary operations.

Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure

Background/Aim: Intima media thickness (IMT) and stiffness of the carotid arteries is related to coronary artery disease, and chronic renal failure patients are at high risk for such diseases. An oral adsorbent, AST-120 (Kremezin; Kureha Chemical Industry, Tokyo, Japan), can delay the progression of chronic renal failure in undialyzed uremic patients. The aim of the present study was to determine whether AST-120 affects carotid artery IMT and pulse wave velocity (PWV) in patients with chronic renal failure not undergoing dialysis. Methods: Fifty patients with non-diabetic chronic renal failure were randomly divided into two groups: 30 patients (18 men and 12 women; mean age 53.5 years; mean serum creatinine 3.2 mg/dl) who were given AST-120 (6.0 g/day) and 20 patients (12 men and 8 women; mean age 52.0 years; mean serum creatinine 3.5 mg/dl) who were not given AST-120. Thirty healthy age-matched subjects (18 men and 12 women; mean age 51.5 years; mean serum creatinine 0.9 mg/dl) were also included. The treatment period was 24 months. IMT and arterial stiffness were measured before and after treatment. Results: The slope of the reciprocal serum creatinine concentration over time became significantly less steep in the AST-120 group than in the non-AST-120 group (p < 0.001). Before treatment, carotid artery IMT differed little between the AST-120 group (0.90 ± 0.22 mm) and the non-AST-120 group (0.88 ± 0.20 mm). IMT in these two groups was significantly greater than IMT in the control group (0.64 ± 0.14 mm) (p < 0.01). Carotid IMT in the AST-120 group decreased slightly but not significantly to 0.84 ± 0.20 mm after 12 months and then significantly after 24 months to 0.78 ± 0.18 mm (p < 0.05). Carotid IMT in the non-AST group showed little change throughout the experimental period. PWV differed little between the AST-120 group (1,980 ± 330 cm/s) and the non-AST group (1,940 ± 360 cm/s) before treatment. PWV values in these two groups were significantly greater than PWV in the control group (1,280 ± 240 cm/s) (p < 0.01). After 12 and 24 months, PWV in the AST-120 group decreased significantly to 1,840 ± 280 cm/s (p < 0.05) and to 1,780 ± 260 cm/s (p < 0.05), respectively; however, PWV in the non-AST group showed a slight increase during the experimental period. Conclusion: The data suggest that AST-120 may reduce arterial stiffness and IMT in non-diabetic chronic renal failure patients before dialysis.

Incipient chordoma : a report of two cases of early-stage chordoma arising from benign notochordal cell tumors

Chordomas are rare malignant bone tumors primarily involving both ends of the axial skeleton that present as destructive bone lesions with a large soft tissue mass. Chordomas were previously believed to arise from notochordal remnants. However, recent studies suggest the possibility that chordomas arise from benign notochordal cell tumors. We present two cases of coccygeal incipient chordoma that strengthen the new hypothesis. The first case was an 83-year-old man who died of prostatic adenocarcinoma. The second case was a 79-year-old man who died of hepatocellular carcinoma. The coccygeal tumors were composed of intraosseous and extraosseous infiltrative lesions. The intraosseous lesions consisted of both benign notochordal cell tumor and incipient chordoma. The extraosseous lesions were consistent with incipient chordoma. In addition, two other small benign notochordal cell tumors were found at a different level in case 1. It is conceivable that pre-existing intraosseous benign notochordal cell tumors transform into incipient chordoma and then extend through the cortex into the surrounding soft tissue. The incidence of incipient chordoma appears much higher than expected because chordomas are rare tumors with an incidence of one case per 1 000 000 persons per year. We suspect that unknown factors transform incipient chordoma into classic chordoma.

Development of colonic neoplasia in p53 deficient mice with experimental colitis induced by dextran sulphate sodium

Background: Several animal models for human ulcerative colitis (UC) associated neoplasia have been reported. However, most neoplasias developed in these models have morphological and genetic characteristics different from UC associated neoplasia. Aims: To establish a new colitis associated neoplasia model in p53 deficient mice by treatment with dextran sulphate sodium (DSS). Methods: DSS colitis was induced in homozygous p53 deficient mice (p53−/−-DSS), heterozygous p53 deficient mice (p53+/−-DSS) and wild-type mice (p53+/+-DSS) by treatment with 4% DSS. Numbers of developed neoplasias were compared among the experimental groups, and macroscopic and microscopic features of the neoplasias were analysed. Furthermore, K-ras mutation and beta-catenin expression were assessed. Results: p53−/−-DSS mice showed 100% incidence of neoplasias whereas the incidences in p53+/−-DSS and p53+/+-DSS mice were 46.2% and 13.3%, respectively. No neoplasias were observed in the control groups. The mean numbers of total neoplasias per mouse were 5.0 (p53−/−-DSS), 0.62 (p53+/−-DSS), and 0.2 (p53+/+-DSS). The number of neoplasias per mouse in the p53−/−-DSS group was significantly higher than that in the other DSS groups. The incidences of superficial type neoplasias were 91.7% in p53−/−-DSS mice, 75.0% in p53+/−-DSS mice, and 33.3% in p53+/+-DSS mice. The K-ras mutation was not detected in any of the neoplasias tested. Translocation of beta-catenin from the cell membrane to the cytoplasm or nucleus was observed in 19 of 23 (82.6%) neoplasias. Conclusions: The p53−/−-DSS mice is an excellent animal model of UC associated neoplasia because the morphological features and molecular genetics are similar to those of UC associated neoplasia. Therefore, this model will contribute to the analysis of tumorigenesis related to human UC associated neoplasia and the development of chemopreventive agents.

Azelnidipine Reduces Urinary Protein Excretion and Urinary Liver-Type Fatty Acid Binding Protein in Patients with Hypertensive Chronic Kidney Disease

Background:Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD). Methods:Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period. Results:Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period. Conclusions:Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

Effect of Polymyxin B-Immobilized Fiber on Blood Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Levels in Acute Respiratory Distress Syndrome Patients

Background/Aims: Metalloproteinase (MMP)-9 plays a role in the pathogenesis of acute respiratory distress syndrome (ARDS). Polymyxin B-immobilized fiber (PMX-F) treatment improves circulatory disturbance and oxygenation in ARDS patients. We aimed to assess whether PMX-F treatment alters the blood MMP-9 and tissue inhibitor of MMP (TIMP)-1 levels in ARDS patients. Methods: Twelve ARDS patients who received PMX-F treatment and 20 healthy control volunteers were included in this study. PMX-F was carried out twice at a rate of 100 ml/min for 2 h with a time interval of 24 h. Blood MMP-9 and TIMP-1 levels were measured before and after PMX-F treatment. We monitored blood pressure and the PaO2/FiO2 (PF) ratio before and after PMX-F treatment. Results: The mortality of ARDS patients after PMX-F treatment was 16.7%. Chest X-ray abnormalities were ameliorated in surviving patients after PMX-F treatment. Systolic and diastolic blood pressure increased significantly after PMX-F treatment (p < 0.01). The PF ratio also increased significantly after PMX-F treatment (p < 0.01). Blood MMP-9 and TIMP-1 levels in ARDS patients (126.4 ± 36.4 and 326.5 ± 52.5 ng/ml) were significantly higher than in controls (34.5 ± 12.5 and 160.5 ± 24.5 ng/ml; p < 0.01). PMX-F treatment reduced these levels significantly (the first treatment: MMP-9 85.4 ± 28.6 ng/ml, p < 0.05, TIMP-1 265.8 ± 36.6 ng/ml, p < 0.05; the second treatment: MMP-9 56.5 ± 18.8 ng/ml, p < 0.01, TIMP-1 220.6 ± 30.5 ng/ml, p < 0.01). Conclusion: These data suggest that MMP-9 and TIMP-1 may play a role in the pathogenesis of ARDS and that PMX-F treatment ameliorated increased MMP-9 and TIMP-1 levels in ARDS patients.

Tumor Necrosis Factor‐α in the Placenta is not Elevated in Pre‐eclamptic Patients Despite its Elevation in Peripheral Blood

Problem:  Tumor necrosis factor‐α (TNF‐α) is present in human placental and uterine cells at the early and late stages of gestation and promotes the regulation of trophoblast growth and invasion. We evaluated whether TNF‐α levels in the placenta and blood of pre‐eclamptic women differed from those with normal pregnancies.

Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner

Synthesis of nitric oxide (NO) can be blocked by inhibition of nitric oxide synthase (NOS) active site with guanidino-substituted analogues of l-arginine such as asymmetric dimethylarginine (ADMA). There is growing evidence that elevation of serum ADMA levels play a role in the progression of atherosclerosis and chronic kidney disease (CKD) in high-risk patients. Further, dyslipidemia contributes to cardiorenal disease as well. However, effects of ezetimibe, a specific inhibitor of cholesterol absorption and widely used drug for the treatment of dyslipidemia, on serum ADMA levels and renal injury remain unknown. In this study, we examined whether ezetimibe treatment decreased serum levels of ADMA, proteinuria and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and l-fatty acid binding protein (l-FABP), markers of oxidative stress and tubular injury, respectively and investigated their relationships in 10 non-diabetic CKD patients with dyslipidemia. Ezetimibe treatment (10mg/day) for 6 months significantly decreased circulating levels of LDL-cholesterol, triglycerides and ADMA, while it increased HDL-cholesterol levels. Further, ezetimibe treatment significantly reduced urinary excretion levels of protein, l-FABP and 8-OHdG. In univariate analyses, serum ADMA levels were correlated with urinary protein, l-FABP and 8-OHdG levels. In multiple stepwise regression analysis, proteinuria was independently correlated with ADMA. Our present study demonstrated for the first time that ezetimibe decreased serum ADMA levels and improved renal injury in non-diabetic CKD patients with dyslipidemia in a cholesterol-independent manner. Ezetimibe may have pleiotropic actions, that is, ADMA-lowering and anti-oxidative effects, that could contribute to renoprotective properties of this lipid-lowering agent.

Concurrent occurrence of gastric adenocarcinoma and duodenal neuroendocrine cell carcinoma: a composite tumour or collision tumours ?

BACKGROUND Neuroendocrine cell (NEC) carcinoma is occasionally accompanied by adenocarcinoma but the relationship between these two morphologically distinct tumours is unclear. Two hypotheses have arisen regarding the mechanism for the association of adenocarcinoma and NEC carcinoma. One is that both are derived from a common multipotential epithelial stem cell. The second hypothesis is that adenocarcinoma and NEC carcinoma arise from a multipotential epithelial stem cell and a primitive NEC, respectively. AIMS To elucidate the relationship between the two histologically distinct tumours, adenocarcinoma of the stomach and NEC carcinoma of the duodenum. PATIENT/METHODS We present a case in which the tumour extended across the pyloric ring, the gastric portion of which revealed adenocarcinoma while the duodenal portion showed argyrophil NEC carcinoma. The two histologically distinct lesions of the tumour were examined by immunohistochemistry and genetic analysis of p53. RESULTS The gastric region was negative for chromogranin A staining but positive for carcinoembryonic antigen (CEA) staining. In contrast, the duodenal region was positive for chromogranin A but negative for CEA. All tumour regions showed a point mutation in p53 gene at exon 7 (GGC (glycine)→GTC (valine) at codon 245). The distal portion of the duodenal tumour showed an additional point mutation inp53 gene at exon 5 (GCC (alanine)→GTC (valine) at codon 129). CONCLUSIONS The two histologically distinct tumours, adenocarcinoma of the stomach and NEC carcinoma of the duodenum, appear to be derived from a common epithelial cell.