Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines.

This is the first report enumerating a superb antiproliferative effect of both sulindac and exisulind on hepatocellular cancer cell lines. The growth inhibition and cytotoxicity of sulindac in human hepatocellular carcinoma cell lines HepG2, Huh-7, and KYN-2 were investigated by studying cell growth, cell cycle distribution, and induction of apoptosis. In the presence of sulindac, there was a marked time- and dose-dependent decrease in cell proliferation and viability. Also, exisulind exhibited a similar growth-inhibitory effect on the KYN-2 cell line. The findings of this study suggest that sulindac exhibits a growth-inhibitory effect on human hepatocellular carcinoma cell lines; therefore, these drugs might serve as an effective tool for hepatocellular carcinoma chemoprevention.

Spontaneous apoptosis in advanced esophageal carcinoma: its relation to Fas expression.

The prognostic importance of spontaneous apoptosis and its correlation with clinicopathological characteristics and Fas expression have yet to be delineated in esophageal carcinoma. Specimens from 65 patients with advanced squamous cell carcinoma of the esophagus were used for immunohistochemical evaluation of Fas, proliferating cell nuclear antigen, and apoptosis. The mean apoptotic index (AI) of 65 tumors was 1.38 +/- 0.99% (range, 0.10-4.49%). Thirty-nine (60.0%) patients had a high AI, and 26 (40.0%) patients had a low AI. Low AI was correlated with advanced tumor stage (P = 0.0197) and weak Fas expression (P = 0.0093). Patients with a low AI had significantly (P = 0.0095) worse survival than those with a high AI. However, by multivariate analysis, low AI alone was not an independent prognosticator. When combined with cellular proliferation index, AI became an independent prognostic factor (P = 0.0283) in this group of patients. Our results suggest that enhanced Fas expression is responsible for high AI in squamous cell carcinoma of the esophagus. High AI, combined with the cellular proliferation labeling index, could be an independent prognostic indicator.

Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer.

Esophageal carcinomas have recently been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. However, the prognostic importance of Fas/FasL and their correlation with clinicopathological characteristics are yet to be delineated in this highly malignant carcinoma. Specimens from 106 esophageal squamous cell carcinoma patients were used for immunohistochemical evaluation of Fas, FasL, and CD8 expressions. Fifty-two (49%) and 34 (32%) patients were positive for FasL and Fas, respectively. There were no associations between FasL expression and clinicopathological characteristics except lymph vessel invasion. Strong FasL expression correlated with significant (P = 0.0011) decrease in tumor nest CD8+ cells. However, neither FasL nor CD8+ had any impact on patient survival. Strong Fas expression was correlated with depth of invasion (40.3% in pT1,T2 versus 20.5% in pT3,T4; P = 0.0308), histological differentiation (45.7% in well versus 25.4% in nonwell; P = 0.0347), and lymph node metastasis (22.6% in positive versus 45.5% in negative; P = 0.0129). Fas expression was one of the independent favorable prognosticators for patients' survival (risk ratio, 3.26; P = 0.0103) in esophageal SCC. Fas expression was an independent prognosticator for recurrence-free survival, whereas FasL expression did not influence the survival in esophageal squamous cell carcinoma. Down-regulation of tumor Fas may be the hallmark of immune privilege for the tumor, thus causing the patients' poorer outcome. Tumor FasL may counterattack the host immune cells to such an extent that the prognosis is not affected.

Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients.

The role of cyclooxygenase-2 (COX-2) in tumor neovascularization of human colorectal carcinoma is yet to be delineated. One hundred colorectal carcinoma specimens were evaluated for COX-2 expression and CD34-stained microvessel density (MVD) by immunohistochemical methods. The relationships between COX-2 expression and clinicopathological feature of the patients, MVD, and survival time were analyzed. Increased COX-2 expression was significantly correlated with pathologically unfavorable findings such as tumor size (> 3.0 cm), tumor differentiation (poor, moderate > well differentiated), number of metastatic lymph nodes (24), and Dukes' stage (Dukes' B, C, and D). Larger number of microvessels congregated around the COX-2-expressing area, and the Spearman rank correlation test showed a strong correlation between COX-2 expression and tumor MVD (P < 0.0001). Patients with COX-2-positive tumors had a significantly (P = 0.037, by log-rank test) shorter survival time than those with negative tumors did. In the multivariate analysis, however, only Dukes' stage and number of metastatic lymph nodes remained as independent prognostic factors. Augmented tumor neovascularization may be one of the several effects of COX-2 responsible for poor prognosis in human colorectal carcinoma patients.

Effect of calmodulin inhibitors on thyroid hormone secretion.

The effect of calmodulin inhibitors, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) and trifluoperazine, on TSH-induced thyroid hormone secretion from rat thyroid was examined in vivo and in vitro. The ip administration of 5 mg W-7 to the rat inhibited T4 and T3 secretion from rat thyroids at 2, 3, and 4 h after the ip injection of 2 IU TSH, and so did the ip injection of trifluoperazine at 3 and 4 h. However, the ip injection of N-(6-aminohexyl)-1-naphthalene sulfonamide as a control substance did not show any significant inhibition of T4 and T3 release. To identify the site of action of calmodulin, the effect of W-7 on (Bu)2cAMP-induced thyroid hormone secretion was tested in vitro. One hundred micromolar W-7 completely inhibited T4 release from the rat thyroid when it was enhanced by TSH or (Bu)2cAMP, suggesting that the inhibitory effect of W-7 is subsequent to cAMP formation. These results suggest that calmodulin may play a role in thyroid hormone secretion from the thyroid, acting beyond cAMP formation.

Effects of thyroid hormone on coenzyme Q and other free radical scavengers in rat heart muscle.

Active oxygen species are reported to cause organ damage. This study was therefore designed to determine the behaviour of antioxidants and free radical scavengers so as to reveal changes in animals in the hyper- and hypothyroid state. Levels of antioxidant factors (i.e. coenzyme Q (CoQ)10, CoQ9 and vitamin E) and free radical scavengers (catalase, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD)) were measured in the heart muscles of rats rendered hyper- or hypothyroid by 4 weeks of thyroxine (T4) or methimazol treatment. Serum levels of CoQ9 and total SOD were also measured. A significant reduction in CoQ9 levels was observed in the heart muscles of both hyper- and hypothyroid rats when compared with control hearts. There was no difference in serum CoQ9 levels in thyroid dysfunction when compared with control animals. Levels of vitamin E in the heart muscles of hyperthyroid rats were significantly increased, and there was no reduction in vitamin E levels in hypothyroid rats when compared with control hearts. GSH-PX levels in the heart muscle were reduced in hyperthyroid rats and increased in hypothyroid rats when compared with control hearts. However, there were no differences in catalase levels in heart muscle between hyper- and hypothyroid rats. The concentration of SOD in heart muscle was increased in hyperthyroid rats and was not decreased in hypothyroid rats compared with control rats, suggesting the induction of SOD by excessive production of O2-. These data suggest that the changes in these scavengers have some role in cardiac dysfunction in the hyper- and hypothyroid state in the rat.

Changes of calmodulin concentration and cyclic 3',5'-nucleotide phosphodiesterase activities in cardiac muscle of hyper- and hypothyroid rats.

To investigate the effect of thyroid hormone on cardiac muscle dysfunction in hyper- and hypothyroid states, we evaluated cyclic 3',5'-nucleotide metabolism by measuring cyclic 3',5'-nucleotide phosphodiesterase activity and calmodulin concentrations in the cardiac muscles of hyper- and hypothyroid rats. Cyclic AMP (cAMP) concentration was significantly high in the cardiac muscle of hyperthyroid rats and low in that from hypothyroid rats compared with control rats. Cyclic AMP and cyclic GMP phosphodiesterase activities were significantly decreased in the soluble fraction of cardiac muscle from hyperthyroid rats and markedly increased in this fraction in hypothyroid rats compared with normal animals. Calmodulin concentration was high in hyperthyroid and low in hypothyroid rats. It was concluded from these findings that low cAMP-phosphodiesterase activity might, in part, bring about the high concentration of cAMP. Calmodulin was significantly high in the cardiac muscle of hyperthyroid rats and the reverse was the case in hypothyroid rats compared with normal rats. The implication is that, in hyper- and hypothyroid states, these changes may play an important role in cardiac function via their effect on cyclic nucleotide and Ca2+ metabolism.

Hormonal regulation of DNA polymerase-beta activity in the rat thyroid gland.

Using hypophysectomized rats, it has been shown that DNA polymerase-beta activity in the adrenal gland and testis is largely influenced by pituitary trophic hormones. Sucrose gradient centrifugation of thyroid extracts revealed three peaks of DNA polymerase-beta activity sedimenting at 3.3S, 7.3S and 12S. Of these, hypophysectomy induced a decrease in the 3.3S DNA polymerase-beta, whereas other molecular forms were affected only slightly. DNA polymerase-alpha and -gamma activities were unaffected by hypophysectomy. These changes in DNA polymerase-beta caused by hypophysectomy were reversed by daily i.p. injection of TSH. Furthermore, stimulation of the thyroid by excess TSH induced by the administration of 1-methyl-2-mercaptoimidazole resulted in an increase of all forms of thyroid DNA polymerase-beta. These results show that the level of DNA polymerase is relatively constant after hypophysectomy but that DNA polymerase-beta in the rat thyroid gland is also modulated by TSH mainly through the change of activity of the polymerase-beta which sediments at 3.3S.

Antiangiogenic therapy of human esophageal cancers with thalidomide in nude mice.

BACKGROUND: Thalidomide (alpha-N-phthalimidoglutarimide) is attracting new attention because of its antiangiogenic effect in corneal neovascularization models. However, the effect of this agent on esophageal carcinoma is yet to be established. METHODS: The human esophageal squamous cell carcinoma strains ES63 and ES80 implanted subcutaneously in nude mice were used to evaluate the antiangiogenic effect of thalidomide (200 mg/kg/d) after daily gavage or intraperitoneal administration. Tumor size was measured, and assessment of microvessel density was performed histochemically with Griffonia simplicifolia lectin I. Characterizations of angiogenic growth factors, vascular endothelial growth factor, basic fibroblast growth factor, and thymidine phosphorylase in ES63 and ES80 tumors were done by immunohistochemical staining and reverse transcription-polymerase chain reaction. RESULTS: ES63 strongly expressed 3 angiogenic factors, but ES80 showed moderate expression of thymidine phosphorylase and only weak or no expression of vascular endothelial grown factor and basic fibroblast growth factor at protein and messenger RNA levels. In ES63 intraperitoneal injection of thalidomide produced significant (P < .05) inhibition of tumor growth, but there was no effect after gastric gavage. Also, a significantly (P < .0005) lower microvessel density was encountered in the intraperitoneal thalidomide group. However, in the ES80 tumor strain thalidomide had no antiangiogenic effect after either intraperitoneal or oral administration. CONCLUSIONS: These data indicate that thalidomide exerts an antiangiogenic effect on solid tumor after intraperitoneal administration. Thalidomide might be one of the hopeful antiangiogenic drugs for solid tumors.

Impact of screening survey of gastric cancer on clinicopathological features and survival: retrospective study at a single institution.

BACKGROUND: Detection of gastric cancer in an early stage is important to improve the prognosis of patients with gastric cancer. This study compared the clinicopathologic characteristics and surgical results in patients with asymptomatic gastric cancer detected by a screening program with those of patients with symptomatic cancer. The efficacy of 2 screening methods (barium meal and endoscopy) was also compared. METHODS: The subjects included 196 patients with asymptomatic gastric cancer detected by screening (screening group) and 612 patients with symptomatic gastric cancer (nonscreening group) treated from 1979 to 1997. The screening group was subdivided into the barium meal study group (n = 150) and the endoscopic study group (n = 46). RESULTS: The incidences of early gastric cancer and 5-year survival rates between the screening and nonscreening groups were 77% versus 29% (P <.0001) and 81% versus 44% (P <.0001), respectively. The endoscopic study appeared to be able to detect smaller gastric cancer in an earlier stage compared with the barium meal study, although no statistical differences in survival rate were noted between these 2 screening methods. CONCLUSIONS: Screening plays an important role in detecting gastric cancer in an early stage and in potentially reducing death attributable to gastric cancer. Endoscopic screening is recommended as the best screening method.

DNA polymerase beta in human thyroid of Graves' disease and thyroid tumors.

We have shown that the level of DNA polymerase beta of rat adrenal cortex is regulated by pituitary trophic hormones and may correlate with their endocrine function. Here we measured DNA polymerase beta activity in human thyroid tissues of various benign and malignant thyroid disorders in order to verify the correlation between DNA polymerase beta activity and endocrine function. In Graves' disease (hyperfunction), the level of DNA polymerase beta per cell was three times higher than in normal thyroid, while in undifferentiated thyroid carcinomas this enzyme level was lower than normal. Furthermore, DNA polymerase beta in the crude extracts of cancer cells showed larger molecular forms, ranging from five to 12S, upon sucrose gradient sedimentation. These observations further support the hypothesis that the activity of DNA polymerase beta correlates, in part, with the functional level of the endocrine organ and with cell differentiation.

Cushing's syndrome induced by hypersecretion of cortisol from only one of bilateral adrenocortical tumors.

A case of Cushing's syndrome induced by the unilateral (right side) dominance of cortisol secretion in the face of bilateral adrenal tumors is reported. The adrenal tumor resected on the right side was a so-called black adenoma and histologically without any findings of nodular hyperplasia. After resection of the adrenal adenoma, no findings of cortisol hypersecretion from the remaining adrenal tumor on the left side were observed until the present, suggesting that the tumor of the left adrenal gland is a nonfunctioning adenoma. These data imply that the adrenal adenomas have primarily developed from the adrenal gland itself, rather than from micronodular hyperplasia by corticotropin stimulation, and that one of these tumors produces excess hormones initially by corticotropin stimulation, but the other remains in cell proliferation.

Alteration of platelet aggregation in patients with thyroid disorders.

To determine whether Graves' disease or primary hypothyroidism influence platelet function, we evaluated platelet aggregation in the platelet-rich plasma (PRP) from such patients. Platelet aggregation induced by adenosine diphosphate (ADP) in blood obtained from patients with untreated Graves' disease was significantly lower than normal, whereas that in patients with untreated primary hypothyroidism was relatively increased. The magnitude of platelet aggregation induced by collagen in both groups of patients resembled that induced by ADP. However, significant differences were evident between the two diseases (P < .05). In addition, we observed a significant inverse correlation between the extent of platelet aggregation and plasma levels of thyroid hormones (triiodothyronine [T3], thyroxine [T4], and free T3). Platelet aggregation returned to normal when the euthyroid condition was obtained in the patients following administration of antithyroid drugs or thyroid hormone. The findings are consistent with the possibility that thyroid hormones influence platelet aggregation partly via inhibition of myosin light-chain kinase (MLCK).

Prognostic factors in T1 and T2 squamous cell carcinoma of the thoracic esophagus.

BACKGROUND: Prognostic indicators in patients with T2 tumor have not been fully understood. OBJECTIVE: To clarify the clinicopathologic characteristics and long-term results of T1 and T2 squamous cell carcinomas of the thoracic esophagus. DESIGN: Consecutive case series. SETTING: Department of surgery in a university hospital. PATIENTS: Of 234 patients with primary squamous cell carcinoma of the thoracic esophagus, 142 patients underwent esophagectomy with curative intent: 97 patients had pT1 and pT2 tumors. INTERVENTIONS: Investigated were clinicopathologic characteristics of 65 of 97 patients with pT1 and pT2 tumors; excluded were 7 patients who died of postoperative complications and another 25 patients who died of causes other than esophageal cancer. MAIN OUTCOME MEASURES: Clinicopathologic characteristics and long-term results. RESULTS: Pathologic tumor stages were pT1 N0 in 23 patients, pT1 N(+) in 7 patients, pT2 N0 in 15 patients, and pT2 N(+) in 20 patients. Fifty patients are alive and free of cancer and 15 patients died of tumor recurrence (1 patient with pT1 N0 tumor, 1 patient with pT1 N[+][+] tumor, 1 patient with pT2 N0 tumor, and 12 patients with pT2 N[+] tumor). The sites of metastatic nodes in 6 survivors with pT1 N(+) tumor were a solitary perigastric node in 4 patients, a solitary mediastinal node in 1 patient, and 2 mediastinal nodes in 1 patient. The 5-year survival rates of patients with pT1 N0, pT1 N(+), and pT2 N0 tumors all exceeded 85%, and the rate of those with pT2 N(+) tumor was 33.9% (pT2 N[+] vs. others: pT1 N0, pT1 N[+], and pT2 N0; P = .003). The factors affecting survival rate by univariate analysis were Borrmann classification (0, 1 vs. 2, 3, 4), tumor size (<4.0 vs. > or =4.0 cm), combined T, N factor (pT2 N[+] vs. others), time of operation (< or =420 vs. >420 minutes), estimated blood loss (<1000 vs. > or =1000 mL), and lymph vessel invasion (marked vs. not marked). Stage pT2 N(+) tumor became a single independent prognostic factor for survival as determined by multivariate analysis (pT2 N[+] vs. others; P = .008). CONCLUSIONS: Stage pT1 N(+) tumors with a few diseased nodes and pT2 N0 tumors are considered to be a group with an excellent prognosis, similar to pT1 N0 tumors. Patients with pT2 N(+) diseases had worse prognoses and thus should have meticulous lymph node dissection and extensive adjuvant therapy.

Esophageal resection in elderly esophageal carcinoma patients: improvement in postoperative complications.

BACKGROUND: Advanced age is considered to be a relative contraindication for radical esophagectomy with a three-field lymph node dissection. METHODS: Preoperative risks, postoperative morbidity and mortality, and long-term survival in 55 elderly patients (> or =70 years) who had undergone extensive esophagectomy for esophageal carcinoma were compared with those of 149 younger patients (<70 years). RESULTS: Elderly patients had worse preoperative cardiopulmonary function and had more frequent postoperative cardiopulmonary complications compared with younger patients (p < 0.05). The postoperative death rate was not statistically different between the elderly (10.9%) and younger groups (5.4%). When the study period was divided into an early and a late phase, the postoperative death rate dropped significantly (p < 0.05) in recent years (1.4%) when compared with the previous era (10.0%). The overall survival rates were not different between elderly and younger patients. CONCLUSIONS: Preoperative cardiopulmonary risk factors and postoperative complications after esophagectomy were more frequently noticed in elderly patients than in younger patients. A dramatic improvement in postoperative death was noticed in recent years. The long-term survival of elderly patients after extended esophagectomy was almost similar to that in younger patients.

Isolation of L-cycloserine from Erwinia uredovora.

An antibiotic which seems to be a cell wall synthesis-inhibitor was isolated from a bacteria strain identified as Erwinia uredovora. The antibiotic was identified with L-cycloserine from its physico-chemical properties. This is the first example for isolation of L-cycloserine as a microbial product.

Gastric resection in the aged (> or = 80 years) with gastric carcinoma: a multivariate analysis of prognostic factors.

BACKGROUND: The incidence of gastric neoplasm is increasing in the elderly population. Therefore, a rational method of treatment for gastric cancer in the elderly should be constituted to improve the survival. The purpose of the present study was to clarify whether the patient's age is an independent prognostic factor and to determine clinicopathological characteristics in the elderly. METHODS: Curative resection of gastric cancer was carried out on 601 patients who were 40 years or older. They were divided into the following two groups: younger patients (between 40 and 79 years old) and elderly patients (80 years or older). The clinicopathologic features of these patients were reviewed retrospectively and multivariate analysis was carried out. RESULTS: The distinguishing features of gastric cancer in the elderly patients were intestinal and mixed types of cancer, distal third stomach dominance in the tumour location, advanced stage of disease, and a low rate of extensive lymph node dissection (D3 or more). Regarding the recurrence site, the liver was the dominant site in the elderly group (25.3% in the younger group vs 54.5% in the elderly group). The 10-year disease-free survival rate of the elderly group was 53.2%, which was significantly worse than that (79.9%) of the younger patients (P = 0.0004). In multivariate analysis, an age of > or = 80 years is an independent prognostic factor, as well as stage, depth of tumour invasion, lymph node metastasis, scirrhous carcinoma, and blood transfusion. CONCLUSIONS: Results indicate that gastric cancer in elderly patients has a poorer prognosis than that in younger patients.