Importance of thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase expression at the invasive front of T3 rectal cancer as prognostic factors

BACKGROUND/AIMS: We evaluated a relationship between postoperative recurrence and thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) expression at the invasive front of T3 rectal cancer. METHODOLOGY: This study was conducted on 61 patients with T3 rectal cancer who underwent surgically curative resection between 1998 and 2002. Paraffin-embedded sections of these patients were immunostained for TP, DPD and TS. Relationship between expression level of the three factors and postoperative recurrence were evaluated. RESULTS: There was no relationship between expression of DPD or TS in the tumor cells and recurrences. Although no relationship was present between expression of TP in the stromal cells around the invasive front of the tumor and postoperative recurrences, there was a strong correlation between expression of TP in the invasive front of the tumor and postoperative recurrence. Moreover, by multivariate logistic regression analysis, TP expression in the tumor cells was the only independent contributory factor for postoperative recurrences (p = 0.021) with an odds ratio of 8.27. CONCLUSIONS: TP expression at the invasive front of the tumor may be an important prognostic factor for T3 rectal cancer, and patients with such a condition may benefit from intensive chemotherapy.     

Thrombomodulin accelerates activated protein C production and inhibits thrombin generation in the plasma of disseminated intravascular coagulation patients.

Thrombomodulin (TM) has been under development as a medicine for disseminated intravascular coagulation (DIC), and is expected to exhibit strong anticoagulant activity by inhibiting thrombin generation via the acceleration of protein C activation. In the present study, we examined the pharmacological action of TM in plasma obtained from DIC patients. TM was found to inhibit thrombin generation and accelerate activated protein C (APC) production at 0.3-30 TM units/ml in plasma obtained from DIC patients irrespective of their underlying disorders. In addition, there was a positive correlation between the inhibition of thrombin generation and the amount of APC produced. Thrombin generation was inhibited by over 50% when the plasma level of APC was increased by more than 0.2 microg/ml. These results indicate that TM inhibits thrombin generation in plasma obtained from DIC patients by accelerating APC production. Moreover, the results imply that the thrombin generation test may be a good method to speculate the efficacy of TM on every patient before the administration of TM.     

Insulin resistance and lichen planus in patients with HCV-infectious liver diseases

Background and Aim: Hepatitis C virus (HCV) causes liver diseases and extrahepatic manifestations, and also contributes to insulin resistance and type 2 diabetes mellitus (DM). The aims of the present study were to examine the incidence of extrahepatic manifestations including lichen planus in HCV‐infected patients and to evaluate the relationship between lichen planus and insulin resistance. Methods: Of 9396 patients with liver diseases presenting to the study hospital, 87 patients (mean age 60.0 ± 11.5 years) with HCV‐related liver diseases were identified and examined for the incidence of extrahepatic manifestations. Insulin resistance and the presence of Helicobacter pylori antibodies were also measured. Results: The prevalence of DM was 21.8% (19/87), hypertension was 28.7% (25/87), thyroid dysfunction was 20.7% (18/87), and extrahepatic malignant tumor was 9.2% (8/87). The prevalence of lichen planus at oral, cutaneous, pharyngeal, and/or vulval locations was 19.5% (17/87). Characteristics of 17 patients with lichen planus (group A) were compared with 70 patients without lichen planus (group B). Prevalence of smoking history, presence of hypertension, extrahepatic malignant tumor, and insulin resistance (HOMA‐IR) were significantly higher in group A than in group B. Significant differences were not observed for age, sex, body mass index, diagnosis of liver disease, alcohol consumption, presence of DM, thyroid dysfunction, liver function tests, or presence of H. pylori infection between the two groups. Conclusions: Infection with HCV induces insulin resistance and may cause lichen planus. It is necessary for an HCV‐infected patient to be assayed for insulin resistance, and to be checked for different extrahepatic manifestations of this infection, particularly lichen planus.     

Primary malignant peripheral nerve-sheath tumor of the common bile duct

Primary malignant peripheral nerve-sheath tumors of the common bile duct are extremely rare. To our knowledge, the published literature contains no previous case report of this disease. Here we report on a 58-year-old Japanese woman with a primary malignant peripheral nerve-sheath tumor of the common bile duct, which was completely resected. A hypoechoic mass was identified in the hepatic hilus, using ultrasonography and computed tomography. Endoscopic retrograde cholangiography revealed a smooth stricture and deviation of the common bile duct. Laparotomy exposed a firm mass around the common bile duct that had not invaded the surrounding tissues. Partial resection of the common bile duct and cholecystectomy were performed as the treatment of choice. The final histopathological diagnosis was malignant peripheral nerve-sheath tumor arising from the wall of the common bile duct.     

Age-related decrease in plasma growth hormone: response to growth hormone-releasing hormone, arginine, and L-dopa in obesity

Aging is associated with a reduction in plasma growth hormone (GH) secretion in non-obese subjects. To determine whether or not age-related changes in plasma GH secretion exist in obese subjects, we measured (a) plasma GH response to growth hormone-releasing hormone (GRH; 1 microgram/kg body wt), arginine (0.5 g/kg body wt), L-dopa (500 mg), and (b) plasma glucose, insulin, and free fatty acids (FFAs) in 26 fasted obese subjects of various ages ranging from 16 to 71 years. Only subjects with a body mass index (BMI; kg/m2) between 30.0 and 39.0 were studied. Six subjects were adolescents, 9 were in their 20s, and 11 were 30 years or older. The mean peak levels of plasma GH in response to GRH, arginine, and L-dopa in obese subjects were 11.3 +/- 2.1, 21.9 +/- 4.4, and 5.2 +/- 0.3 ng/mL in adolescents, 8.2 +/- 1.6, 9.1 +/- 1.5, and 3.1 +/- 0.6 ng/mL in those in their 20s, and 4.5 +/- 0.4, 7.3 +/- 1.4, and 2.8 +/- 0.3 ng/mL in those 30 years or older, respectively, showing a significant decrease in peak GH level with advancing age (P less than .05 to P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathogenesis of Focal Cytoplasmic Necrosis of the Smooth Muscle Cells in Hypertensive Rat Arterial Media

Hypertensive rat arteries exhibited severe medial smooth muscle cell injury and necrosis. Electron microscopic observations showed the smooth muscle cells of these arteries exhibited characteristics of focal cytoplasmic necrosis forming new cytodemarcating membrane between the healthy cytoplasm and necrotic cytoplasm. When the focal necrotic cytoplasm disappeared from the injured smooth muscle cells, it left it with a moth-eaten leaf-like appearance (moth-eaten necrosis). At an advanced stage of injury, smooth muscle cells changed to islet-like cell bodies with newly formed basement membranes around them, and further islet-like cell bodies and cell debris disappeared leaving lamellar and reticular basement membranes.In hypertensive rats injected with nitroblue tetrazolium (NBT), formazan deposits were observed in the medial cells and nitrotyrosine, a biomarker of peroxynitrite, were immunohistochemically observed in the arterial media. Nick-end positive extranuclear small granular bodies, which might have derived from focal necrotic cytoplasm and nucleus, were detected in the arterial media using DNA nick-end labeling method. Based on electron microscopical and histochemical findings, we conjectured that the focal cytoplasmic necrosis of the smooth muscle cells in the arterial media depended on injury arising from mitochondria-derived oxidants.     

Changes in oral antidiabetic prescriptions and improved glycemic control during the years 2002–2011 in Japan (JDDM32)

Aims/Introduction

Six kinds of oral antidiabetic drugs (OADs), including the new dipeptidyl peptidase 4 (DPP‐4) inhibitors, are available. The present study aimed to define trends within the prescribing patterns of OADs, as well as changes in glycemic control in Japan over a 10‐year period from 2002 to 2011.

Materials and Methods

We carried out a cross‐sectional study using data of type 2 diabetes mellitus patients from 24 clinics for 2002, 2005, 2008 and 2011. OAD use was analyzed combined with clinical data.

Results

Sulfonylureas (SUs) were the most commonly used OAD, but their use for monotherapy markedly decreased over the study period. Biguanides (BGs) were the second most commonly used OAD, and their prescribing rate increased both for mono‐ and combination therapy. DPP‐4 inhibitors (DPP‐4I), released in 2009, were the third most commonly prescribed OAD in 2011 both for mono‐ and combination therapy. Among combination therapies, two OADs were mostly prescribed, but the use of three OADs and four OADs in 2011 was two‐ and 14.8‐fold those in 2002. These trends were accompanied by an improvement in average glycated hemoglobin from 7.5 ± 1.2% in 2002 to 7.1 ± 0.9% in 2011.

Conclusions

The OAD prescribing trend has moved away from monotherapy with SUs and toward combination therapies to achieve better glycemic control. Increased use of BGs and DPP‐4I was predominant in 2011. These trends were accompanied by an improvement of the glycated hemoglobin level.