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Purpose: Two taxane analogs, BMS-184476 and -188797, were evaluated for their in vitro cytotoxicity and in vivo antitumor activity, and compared with paclitaxel and occasionally docetaxel (Taxotere).Methods: Cytotoxicity was assessed in vitro using a panel of human tumor cell lines. Several different murine and human tumor models were used in vivo to evaluate the taxane analogs.Results: Both compounds were found to have cytotoxic potency similar to paclitaxel and to partially overcome two different forms of paclitaxel resistance. BMS-184476 was found to be clearly superior to paclitaxel in three human xenograft tumor models: A2780 ovarian carcinoma; HCT/pk, a moderately paclitaxel-resistant colon carcinoma; and L2987 lung carcinoma. Additionally, in the clinically derived TAXOL-unresponsive ovarian carcinoma, HOC79, BMS-184476 performed slightly better than paclitaxel and Taxotere. BMS-184476 and paclitaxel were inactive in two murine model systems, M5076 sarcoma and the paclitaxel-resistant M109/txlr lung carcinoma. Against the parental M109 tumor, both BMS-184476 and paclitaxel performed comparably. BMS-184476 was never found to be inferior to paclitaxel. The other taxane analog, BMS-188797, displayed efficacy superior to paclitaxel in four in vivo tumor models: HOC79, HCT/ pk, M109, and L2987 carcinomas. Like paclitaxel and BMS-184476, BMS-188797 was inactive versus M5076 sarcoma.Conclusions: Two new taxane analogs were characterized as superior to paclitaxel or Taxotere in several in vivo tumor models. Both BMS-184476 and -188797 are currently in phase I or II clinical trials. [ABSTRACT FROM AUTHOR]

Background: Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by N[sup G]-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (~25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. Results: As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). Conclusions: Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity. [ABSTRACT FROM AUTHOR]

Background: Chondroblastoma of bone is a rare lesion, and few large series have been reported. The purpose of this paper is to report forty-seven cases treated by one group of surgeons and to identify factors associated with more aggressive tumor behavior.Methods: Seventy-three patients with chondroblastoma of bone were treated between 1977 and 1998. We were able to obtain historical data, imaging studies, histological findings, and adequate personal or telephone follow-up to determine the outcome for forty-seven patients.Results: The lesions were distributed widely in the skeleton, but most were in the epiphyses or apophyses of the long bones, especially the proximal part of the tibia (eleven tumors) and the proximal part of the humerus (ten tumors). The principal presenting symptoms were pain and limitation of movement. The treatment consisted of a variety of procedures, but the majority of the patients had intralesional curettage and packing with allograft or autograft bone chips or polymethylmethacrylate. Most of the patients had an excellent functional result, although in three osteoarthritis developed in the adjacent joint. Seven patients (15 percent) had a local recurrence; three of them had a second recurrence and one, a third recurrence. One patient died of widespread metastases, and another who had metastases to multiple sites was alive and disease-free after aggressive treatment of the metastatic lesions.Conclusions: While the size of the lesion, the age and gender of the patient, the status of the growth plate, and an aneurysmal-bone-cyst component to the tumor had no significant effect on the recurrence rate, lesions around the hip (the proximal part of the femur, the greater trochanter, and the pelvis) accounted for the majority (five) of the seven recurrent tumors and one of the two metastatic lesions. [ABSTRACT FROM AUTHOR]

To investigate the postprandial gallbladder motility, including emptying and refilling, in cirrhotic patients and to evaluate the relationship to the presence of gallstones and various humoral mediators, 82 patients with liver cirrhosis and 40 age- and sex-matched healthy subjects were enrolled into this study. Postprandial gallbladder volumes were measured with ultrasonography every 15 min for 2 hr. Plasma levels of estradiol, testosterone, substance P, and nitrate/nitrite were also measured. Cirrhotic patients showed a higher prevalence of gallstones than healthy subjects (41% vs 15%, P = 0.003), and the prevalence increased with the progression of liver cirrhosis (Child-Pugh class A: 26%, B: 44%, and C: 65%, P = 0.02). Plasma levels of estradiol, testosterone, and substance P, and nitrate/nitrite and estradiol/testosterone ratios were not different between cirrhotic patients with and without gallstones. However, postprandial refilling of the gallbladders was significantly impaired in patients with cirrhosis, especially in those combined with gallstones. There was no significant difference in the postprandial gallbladder motility between cirrhotic patients with and without elevated plasma levels of estradiol, testosterone, and substance P and nitrate/nitrite, and estradiol/testosterone ratios. Gallstones were common in patients with liver cirrhosis and the prevalence increased with the progression of liver diseases. Sex hormones, substance P, and nitrate/nitrite did not play major roles in the formation of gallstones in cirrhotic patients. Refilling of the gallbladder was significantly impaired in patients with liver cirrhosis, especially in those with gallstones, and may play an important role in the pathogenesis of gallstones. [ABSTRACT FROM AUTHOR]

Background: Hyposensitivity to vasopressin is a well-documented phenomenon in animals with portal hypertension and patients with cirrhosis and hemorrhage. Similar findings exist with infusion of glypressin (a long-acting vasopressin analogue), and this phenomenon could be ameliorated by inhibition of nitric oxide (NO) synthase. Besides NO, excessive formation of prostacyclin (PGI[sub 2]) has been shown to play an important role in the development of hyperdynamic circulation and the mediation of hyporeactivity to vasoconstrictors in portal-hypertensive states. This study was designed to investigate whether the blockade of PGI[sub 2] activity by indomethacin infusion could enhance the portal-hypotensive effect of glypressin in portal-hypertensive rats with bleeding. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Fourteen days after operation systemic and portal hemodynamics were measured in stable or bleeding PVL rats receiving intravenous glypressin (0.07 mg/kg) or indomethacin (5 mg/kg) followed by glypressin infusion. In rats with a hypotensive hemorrhage 4.5 ml of blood was withdrawn, and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. Results: Splanchnic hyposensitivity to glypressin was shown in hemorrhage-transfused PVL rats. Indomethacin infusion did not cause significant systemic and portal-hemodynamic changes in bleeding PVL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin and potentiated the increases in mean arterial pressure induced by glypressin infusion in bleeding PVL rats. Conclusions: The improvement of splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension by the administration of indomethacin suggests that PGI[sub 2] has in the development of this hyposensitivity. [ABSTRACT FROM AUTHOR]

Background: Spider angioma is a common sign in patients with liver cirrhosis, but the pathogenesis is still unclear. Alcohol and hyperestrogenemia are both possible etiologies. This study was designed to investigate the relationship of spider angiomas in patients with liver cirrhosis to alcohol, liver function test results, and plasma levels of sex hormones. Methods: Eighty-two patients with liver cirrhosis and 18 healthy subjects were enrolled in this study. The number, size, and location of the spider angiomas were recorded for all subjects. Plasma levels of estradiol and testosterone were measured. Results: Cirrhotic patients had significantly higher estradiol/testosterone ratios (26.8 ± 5.1 × 10[sup -3] versus 8.8 ± 2.0 × 10[sup -3]; P = 0.002) than healthy controls. Twenty-seven (33%) of the 82 cirrhotic patients had spider angiomas. Cirrhotic patients with spider angiomas were younger (56 ± 3 versus 66 ± 1 years; P = 0.002) and had higher serum bilirubin levels (3.3 ± 0.6 versus 1.7 ± 0.2 mg/dl; P = 0.002), longer prothrombin time (16.8 ± 0.8 versus 14.8 ± 0.4 sec; P = 0.01), and higher prevalence of alcoholism (41% versus 20%; P = 0.04) than those without. Stepwise logistic regression showed that alcoholism and serum bilirubin level were the only significant and independent predictors associated with the presence of spider angiomas in cirrhotic patients (odds ratio = 3.5; 95% confidence interval = 1.2-10.8; P = 0.03, and odds ratio = 2.8; 95% confidence interval = 1.3-5.7; P = 0.006, respectively). Conclusions: Alcoholism and impaired liver function are important predictors of the presence of spider angiomas in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Endoscopic variceal ligation is widely accepted as the optimum endoscopic treatment for esophageal variceal hemorrhage. However, the rebleeding course and long-term outcome of patients with esophageal variceal hemorrhage after ligation have been poorly defined. Therefore, we conducted a long-term follow-up study to delineate the outcome of ligation and compare it with that after sclerotherapy. Methods: One hundred and eighty-five liver cirrhotic patients with endoscopically proven esophageal variceal hemorrhage were randomized to undergo endoscopic variceal sclerotherapy or ligation. These patients received regular follow-up and detailed clinical assessment. Results: Two patients developed hepatoma within 6 months of entry in each group and were excluded. Another six patients in the sclerotherapy group and seven patients in the ligation group were excluded because of poor compliance or lost to follow-up. Therefore, 84 patients in each group were analyzed. In this long-term follow-up (55.3 - 12.5 months) the rebleeding rate for ligation was lower than that for sclerotherapy, regardless of whether the rebleeding was analyzed by patient number or Kaplan-Meier analysis. With regard to the rebleeding risk of various periods, the sclerotherapy risk was higher than that of ligation within 4 weeks of the initial endoscopic treatment or before variceal eradication. Multifactorial analysis showed hematemesis, poor hepatic function, and sclerotherapy were the risk factors determining rebleeding. The annual hepatocellular carcinoma incidence was 4.9%. There was no difference in survival between sclerotherapy and ligation. Multifactorial analysis showed that poor hepatic function was the only factor determining survival. Conclusions: The rebleeding risk was higher in sclerotherapy than in ligation before variceal eradication, especially within 4 weeks of the initial endoscopic treatment. Long-term survival was dependent on hepatic reserve regardless of the treatment method. [ABSTRACT FROM AUTHOR]

The objective of the present study was to investigate the in vivo effects of different doses of 17β-estradiol (E2) and testosterone (T) on the levels of plasma and pituitary gonadotropin II (GTH II) in 2-year-old black porgy, Acanthopagrus schlegeli, during the spawning season. Male fish were distributed among 7 groups (n = 49), control, E2or T (with 3 doses, 2.4 ng, 72 ng and 2.2 μg g−1 body weight). Fish were injected with the respective vehicle or different doses of E2 or T on days 1 and 14. Plasma E2 levels were significantly increased in the 72 ng E2 group on days 8 and 14. Plasma vitellogenin levels were significantly higher in the 72 ng E2 group on days 14 and 20, and 2.2 μg E2 group on days 8, 14 and 20 than those in the control group. Plasma GTH II concentrations were significantly higher in the 2.2 μg E2 group than in the control and other E2groups on days 8, 14 and 20. Pituitary GTH II contents was significantly higher in the 7.2 ng E2 group compared to the control and other E2groups on day 20. Plasma GTH II concentrations were similar in the control and all the T groups on days 8, 14 and 20. None of the doses of T treatment stimulated pituitary GTH II content on day 20, although plasma vitellogenin levels were elevated. It is concluded that GTH II synthesis and secretion in black porgy is stimulated by an estrogen-specific effect. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA) and chemotherapy have been shown to have better outcome than those treated with conventional chemotherapy alone. However, the biological characteristics of leukemic cells and their clinical implications in patients treated with ATRA have not been well established. In this study, the biological and clinical features of 30 APL patients were reported. The risk factors for relapse and for occurrence of retinoic acid (RA) syndrome, which might cause morbidity or mortality of patients after ATRA treatment, were also analyzed. All patients showed 15;17 translocation by cytogenetic and/or gene analysis. Patients in this study had higher white blood cell (WBC) counts and a higher incidence of additional abnormalities than those from other areas. The ratio of long (L) form to short (S) form PML-RAR alpha fusion transcript was 1.8:1, a value lower than that of Latino patients but higher than that of Italians. Leukemic cells from four patients showed coexpression of T cell-associated antigen CD2 which was highly correlated with S form fusion transcript. Nine (36%) of the 25 patients treated with ATRA developed RA syndrome; all but one were successfully controlled by corticosteroid. Complete remission (CR) rate was 84%. Patients with high WBC counts tended to develop RA syndrome and had increased risk of relapse. Isochromosome for the long arm of the derivative chromosome 17, ider(17q), as an additional chromosomal abnormality was also associated with poor outcome in this study. In conclusion, APL in this study showed some different biological characteristics compared with those reported in other areas. High WBC count was a risk factor for relapse and development of RA syndrome after ATRA treatment. The prognostic implication of the presence of ider(17q) needs further clarification. [ABSTRACT FROM AUTHOR]