A series of substituted oxindole derivatives was synthesized and evaluated for growth hormone (GH) releasing activity using cultured rat pituitary cells. (+)-6-Carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity (EC(50) = 3.0 nM), while the other enantiomer 37R had reduced activity. The absolute configuration of 37S was confirmed by X-ray crystallographic analysis. Compound 37S showed a good pharmacokinetic profile in rats with 28% oral bioavailability at 10 mg/kg and excellent in vivo activity as evidenced by a significant weight gain after 4 days of oral administration at 10 mg/kg twice a day. Compound 37S displaced the binding of (35)S-MK-677 to human GHS-R with an IC(50) value of 1.2 +/- 0.2 nM.

In patients with advanced biliary malignancies a chance of curability is obtained by performing only major hepatectomy with concomitant pancreatoduodenectomy. This aggressive procedure carries two major risks: hepatic failure and pancreatic anastomotic leakage. Ten patients with advanced biliary malignancies were treated by major hepatectomy with pancreatoduodenectomy. Nine patients underwent right portal venous embolization before hepatectomy. Complete external drainage of pancreatic juice followed by second-stage pancreatojejunostomy was performed in five patients. Three of these five underwent concomitant resection of the hepatic artery, portal vein, or both. Pancreatogastrostomy was chosen for five patients who required no concomitant vascular resection. There were no hospital deaths or hepatic failures. Leaks from pancreatogastrostomy occurred in two patients. In five patients who underwent external drainage of pancreatic juice, there were no complications related to the pancreatic stump, although one had ischemic necrosis of the jejunal segment and laparotomy was repeated. Mean survival time was 31.8 months (range 13-59 months). Portal venous embolization and complete external drainage of pancreatic juice followed by late stage pancreatojejunostomy are recommended surgical procedures for patients undergoing major hepatectomy with pancreatoduodenectomy, especially when concomitant vascular resection is required for curative resection of the tumor in patients with a soft pancreatic parenchyma and thin pancreatic duct.

Perineural invasion is associated with tumor spreading and an unfavorable prognosis in a variety of cancers. Recently, neural cell adhesion molecule (NCAM) has been reported to be affinitive to neural tissues, which suggests some relationship between NCAM and perineural invasion. This study was designed to elucidate the role of the expression of NCAM on the development of perineural invasion in bile duct cancer. A histopathologic study was performed on 24 patients with bile duct carcinoma who underwent resections. The overall incidence of NCAM expression in the resected specimen was 66.7% and that of perineural invasion was 87.5%. Furthermore, NCAM expression was shown to be positive in 16 (76%) out of 21 cases in whom perineural invasion was observed. A significant positive correlation was found between the expression of NCAM and perineural invasion in bile duct cancer. These results highlight an important role of NCAM in the development of perineural invasion in bile duct cancer.

Although only 2 cases were surgically intervened with limited experience, the present novel LECS approach allowed a reliable, adequate resection of tumors located in the duodenum, with abbreviated operation times (156-179 versus 202-229 minutes), minimal bleeding, less postoperative stress imposed on the surgeons, and an uneventful postoperative course, compared to conventional surgical methods.

SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6⋅3 3⋅4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GHreleasing hormone antagonist. SM-130686 dosedependently inhibited the binding of radiolabeled ligand, 35 S-MK-677, to human GHS receptor 1a (IC 50 =1⋅2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19⋅5 2⋅1 and 18⋅1 7⋅5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor.In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.

Growth hormone (GH) is known to interact with adipose tissue and to induce lipolysis. Adipocytes produce leptin which regulates appetite and energy expenditure. In order to elucidate the role of GH in leptin production, we studied the effect of GH on leptin gene expression and body fat in fatty Zucker rats, a model of obesity with resistance to both leptin and insulin. Recombinant human GH administered subcutaneously at 0·5 mg/kg per day (low dose) as well as at 1·65 mg/kg per day (high dose) reduced leptin mRNA levels in epididymal fat tissue but not in subcutaneous fat tissue after 7 days. GH administration only at the high dose reduced percentage body fat. Insulin-like growth factor-I infusion (200 µg/kg per day) did not change percentage body fat or leptin mRNA levels in epididymal fat. These observations suggest that GH directly interacts with adipose tissue and reduces leptin gene expression in visceral fat tissue.

To clarify the role of neural cell adhesion molecule (NCAM) in perineural invasion, NCAM expression was studied by immunohistochemical staining in 26 cases with gallbladder cancer. In gallbladder cancer, the incidence of perineural invasion and that of positive NCAM expression was 42% and 31%, respectively, which are less frequent than those of bile duct cancer in our previous report. Perineural invasion was observed in 88% of the patients with positive expression of NCAM and in 22% of those with negative expression. The former is similar to that of bile duct cancer but the latter is significantly lower. Eighty percent of the cancer cells that invaded the perineural space were positive for NCAM, when the primary tumor was positive for NCAM expression. Therefore, in gallbladder cancer, positive cells in NCAM expression likely invade the perineural spaces. However, the perineural invasion of negative cells in NCAM expression is not likely to occur as compared to bile duct cancer. In conclusion, perineural invasion in gallbladder cancer is not as common as in bile duct cancer, but the role of NCAM in perineural invasion is more important in gallbladder cancer than in bile duct cancer.

Laparoscopic TAPP inguinal hernia repair after RALP was safe and effective. TAPP inguinal hernia repair may be a valuable alternative to open hernioplasty.