Clinicopathologic features of ampullary carcinoma without jaundice

GOALS: To evaluate clinicopathological features of ampullary carcinoma without jaundice. BACKGROUND:: Obstructive jaundice is the most common symptom of patients with ampullary carcinoma. However, some patients with ampullary carcinoma do not have jaundice at the time of diagnosis. STUDY: Clinicopathologic findings of 23 patients with ampullary carcinoma showing no visible jaundice (serum total bilirubin <3.0 mg/dL) and 38 patients with ampullary carcinoma showing jaundice at the time of diagnosis were retrospectively compared. RESULTS: Fifteen of 23 patients with nonjaundiced ampullary carcinoma complained of fever and/or abdominal pain. Five asymptomatic patients were found to have a dilated bile duct on screening ultrasound or to have a tumor-like swelling of the papilla of Vater during routine upper gastrointestinal endoscopy. There was no significant difference in age, sex, size, macroscopic type, histologic type, rates of duodenal invasion, pancreatic invasion, and lymph node metastasis, and prognosis between the two groups. The cumulative 5-year and 10-year survival rates of nonjaundiced patients were 70.2% and 49.0%, compared with 33.6% and 29.4% of jaundiced patients. Ten of the 23 nonjaundiced ampullary carcinomas (43%) were in Stage I, whereas 4 of the 38 jaundiced ampullary carcinomas (11%) were in Stage I (P < 0.01). Mechanisms of nonjaundice in ampullary carcinoma were suspected to be determinant by the infiltrating pattern of the carcinoma to the lower portion of the bile duct. CONCLUSIONS: Mechanisms of nonjaundice in ampullary carcinoma might be determined by the infiltrating pattern of the carcinoma to the lower portion of the bile. As a greater number of nonjaundiced ampullary carcinomas were in an early stage, detection of them may provide an improved clinical outcome.     

Regulation of VEGF-A, VEGFR-I, thrombospondin-1, -2, and -3 expression in a human pituitary cell line (HP75) by TGFbeta1, bFGF, and EGF

Pituitary tumors are highly vascular neoplasms, which suggest an important role of angiogenesis in pituitary tumor growth. We used the human pituitary cell line (HP75) to examine the effects of the growth factors TGFβ1, bFGF, and EGF on cell growth, and on the regulation of the pro-angiogenic growth factor VEGF-A and the VEGFR-I and the anti-angiogenic molecules thrombospondin (TSP) TSP-1 and TSP-2 along with TSP-3. Real-time RT-PCR was used to measure mRNA levels, and Western blot was used to analyze TSP-1 and TSP-2 protein levels. TGFβ1 treatment (1×10⁻⁹ M) increased VEGF-A mRNA levels significantly (p<0.05) after 4 and 24 h of treatment. TGF β1 treatment decreased VEGF-R mRNA levels after 96 h of treatment (p<0.05). After 96 h of treatment, TSP-1 and TSP-2 mRNA levels were significantly increased (p<0.05) by TGFβ1 treatment, which also inhibited HP75 cell growth. Basic FGF also increased TSP-1 mRNA levels after 96 h of treatment, but did not regulate growth of the pituitary tumor cells. Basic FGF and EGF did not modulate changes in VEGF-A mRNA levels after 4 and 24 h of treatment, but EGF increased VEGF-A significantly (p<0.05) after 96 h of treatment. These results indicate that TGFβ1 treatment may regulate angiogenesis in pituitary cells by initially increasing levels of pro-angiogenic VEGF-A and then stimulating the anti-angiogenic molecules TSP-1 and TSP-2 levels.     

Dominant-Negative Rho, Rac, and Cdc42 Facilitate the Invasion Process of Vibrio parahaemolyticus into Caco-2 Cells

To clarify the invasive process of Vibrio parahaemolyticus, an invasion assay was performed using cells expressing dominant negative small GTPases of the Rho family. This assay showed that the dominant negative host phenotype facilitates bacterial invasion, suggesting that the mechanism of V. parahaemolyticus invasion differs from that reported for other invasive bacteria.     

Immunohistochemical analysis of 14-3-3 sigma and related proteins in hyperplastic and neoplastic breast lesions, with particular reference to early carcinogenesis

In order to confirm the role of 14-3-3 sigma (sigma) as a tumor suppressor in breast carcinogenesis, we have studied the expression of 14-3-3sigma immunohistochemically in usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) breast lesions. Immunostaining for estrogen receptor alpha (ERalpha), p53 and estrogen-responsive RING finger protein (Efp) was also carried out. Immunohistochemically, expression of 14-3-3sigma was seen in 92% UDH lesions and gradually decreased from 65% in DCIS to 23% in IDC. The expression of ERalpha decreased gradually from UDH to DCIS to IDC, while p53 showed an inverse staining pattern to that of ERalpha. The expression of Efp showed no significant difference among the three breast lesions. Hence, the present immunohistochemical study confirmed 14-3-3sigma as a tumor suppressor in breast carcinogenesis. A similar immunohistochemical analysis was then carried out on columnar cell hyperplasia with atypia (CCHA), in which the expression pattern of tumor suppressor 14-3-3sigma, ERalpha and p53 suggested that it might be possible that CCHA is a precancerous lesion.     

Genetic polymorphism of aldehyde oxidase in Donryu rats.

One of major metabolic pathways of [(+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine] (RS-8359), a selective and reversible monoamine oxidase type A inhibitor, is the aldehyde oxidase-catalyzed 2-hydroxylation at the pyrimidine ring. Donryu rats showed a dimorphic pattern for the 2-oxidation activity with about 20- to 40-fold variations in the Vmax/Km values between a low and a high activity group. The rats were classified as extensive metabolizers (EM) and poor metabolizers (PM) of RS-8359, of which ratios were approximately 1:1. One rat among the EM rats of each sex showed extremely high activity, and they were referred to as ultrarapid metabolizers. There was no significant difference in the expression levels of mRNA of aldehyde oxidase between the EM and PM rats. Analysis of nucleotide sequences showed four substitutions, of which the substitutions at 377G>A and 2604C>T caused 110Gly-Ser and 852Ala-Val amino acid changes, respectively. Amino acid residue 110 is located very near the second Fe-S center of aldehyde oxidase. Its change from nonchiral Gly to chiral Ser may result in a conformational change of aldehyde oxidase protein with the shift of isoelectric point value from 5.0 in the EM rats to 6.2 in the PM rats. The 110Gly-Ser amino acid substitution (377G>A) may be primarily responsible for the variations of aldehyde oxidase activity observed in Donryu rats, in addition to the difference of expression levels of aldehyde oxidase protein. If a new drug candidate is primarily metabolized by aldehyde oxidase, attention should be given to using a rat strain with high aldehyde oxidase activity and small individual variation.     

Two-dimensional and Doppler echocardiographic assessment of variably shaped ductus arteriosus by the parasternal approach

Summary Parasternal two-dimensional and Doppler echocardiography were compared with angiographic, surgical, and postmortem data in 213 patients with various forms of congenital heart disease for its accuracy in determining patency and anatomy of the ductus arteriosus (DA). The age range of the examined patients was from 1 day to 4 years (mean, 7.4 months). Echocardiography was always performed before any invasive procedure. An adequate window for imaging the DA was obtained by parasternal, two-dimensional echocardiography in 209 patients (98%). A persistent ductus arteriosus (PDA) was detected by invasive methods in 79 of 209 patients (38%), and by two-dimensional and Doppler echocardiography in 76 (sensitivity, 96%; specificity, 100%). The echocardiographic and angiographic findings agreed closely as to the duct's morphology. Our technique permits an accurate visualization of the duct in neonates, infants, and small children with various forms of congenital heart disease.     

Prevention by acetylsailcylic acid of liver cirrhosis and carcinogenesis as well as generations of 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances caused by a choline-deficient, L-amino acid-defined diet in rats

Effects of acetylsailcylic acid (ASA) (aspirin) on the pathogenesisof fatty liver, cirrhosis and hepatocarcinogenesis caused bya choline-deficient L-amino acid-defined (CDAA) diet were examinedin male Fischer 344 rats fed a CDAA diet supplemented with 0,0.1, 0.2, 0.4 or 0.8% ASA for 30 weeks. ASA at concentrationsof >0.2% prevented the development of both cirrhosis andpreneoplastic and neoplastic nodules, but without any directlyassociated prevention of fatty changes. ASA also prevented hepatocyteproliferation and the generation of thiobarbituric acid-reactivesubstances and 8-hydroxydeoxyguanosine caused by feeding theCDAA diet, analyzed, respectively, after 1, 12 and 12 weeks.The results clearly indicate that the anti-inflammatory drugASA, which is not a lipotropic factor, can prevent the pathogenesisof cirrhosis and hepatocarcinogenesis caused by a CDAA diet,which is possibly partly associated with the prevention of reactiveoxygen species production.     

Different Roles of 8-Hydroxyguanine Formation and 2-Thiobarbituric Acid-reacting Substance Generation in the Early Phase of Liver Carcinogenesis Induced by a Choline-deficient, l-Amino Acid-defined Diet in Rats

The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline-deficient, l -amino acid-defined (CDAA) diet by examining the effects of the antioxidant N, N' -diphenyl- p -phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8-hydroxyguanine (8-OHGua) for DNA and that of 2-thiobarbituric acid-reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S -transferasc (EC 2.5.1.18) placental form (GSTP)- and/or γ-glutamyltransferase (GGT, EC 2.3.2.2)-positive lesions and levels of 8-OHGua and TBARS were determined. The GSTP-positive lesions of 0.08 mm² or larger were all stained positively for GGT as well in cross-sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP-positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8-OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8-OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.