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Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma. A possible marker for serosal invasion and metastasis.

BACKGROUND: Expression of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in tumor tissue from patients with gastric carcinoma has been reported to be related to disease progression. However, to the authors' knowledge the clinical significance of plasma TIMP-1 concentrations in these patients has not been clarified. METHODS: Concentrations of TIMP-1 protein were examined by enzyme-linked immunoadsorbent assay in plasma samples from 149 patients who underwent resection of their primary tumors and from 18 patients with nonresected or recurrent disease. RESULTS: In the 149 patients whose primary tumors were resected, plasma TIMP-1 concentration was associated significantly with a variety of pathologic factors including macroscopic type, depth of invasion, lymph node and peritoneal metastases, vessel invasion, pattern of tumor infiltration into surround ing tissue, and disease stage. Plasma TIMP-1 concentration was significantly higher in patients with serosal invasion, lymph node metastasis, peritoneal dissemination, or liver metastasis than in those without these factors. Neither carcinoembryonic antigen (CEA) nor CA 19-9 concentrations appeared to be related to these measures of disease progression. In the 18 patients with nonresected or recurrent disease, TIMP-1, CEA, and CA 19-9 were similarly sensitive in predicting peritoneal, liver, and lymph node metastases. The combination of these three factors was able to detect 73.3% of patients with peritoneal metastasis, 83.3% of patients with liver metastasis, and 88.9% of patients with disease recurrence. CONCLUSIONS: In patients with gastric carcinoma, plasma concentration of TIMP-1 appears to correlate with both serosal invasion and metastasis.

CA-19-9 Antigen↗

Contributions to an analysis of the avian vitelline membrane's potential to promote outgrowth of the yolk sac-serosal membrane.

Explanted blastoderms of freshly laid chicken eggs expand their area during the first 44-45 hours of incubation by a factor of at least 11 if they are placed with the epiblast on the inner surface of explanted fresh chick vitelline membrane and provided with chick egg extract. This expansion is due essentially to the spreading of the yolk sac-serosal membrane. On turkey and duck membrane the expansion factor is about 6 and 3.8 respectively under otherwise identical conditions, but 1.9 only on a semisolid nutrient agar plate. Only the inner surface of the vitelline membrane has this growth-promoting potential, which markedly and progressively declines during incubation in ovo because of systemic factors rather than because of a direct influence by the outgrowing yolk sac-serosal membrane. Trypsinization of fresh chick vitelline membrane (1% trypsin 3 hours) reduces the growth-promoting potential to about 40% of its normal strength. The outgrowth of the extraembryonic tissues on vitelline membrane is better supported in the presence of a species' own egg extract than by extract from another species.

Animals↗

Role of intraoperative assessment of lymph node metastasis and serosal invasion in patients with gastric cancer.

The clinical diagnoses of nodal status (N) and tumor invasion (T) were performed intraoperatively during 1499 consecutive operations for gastric carcinoma and compared with subsequent pathologic diagnoses. An accurate macroscopic diagnosis of N stage was difficult; overall accuracy was only 56.6%. Intraoperative assessment of T stage (particularly of serosal invasion) was correct for 93.2% of early stages of the disease with invasion confined to the mucosa or submucosa (pT1) when the pathologist assessed the T stage in the resected specimen, for 95.6% of advanced tumors invading the serosa (pT3), but for tumors of an intermediate stage with invasion involving the muscularis propria or the subserosa (pT2) in only 41.9% of cases. Macroscopic overestimation occurred in 58.1% of cases with pT2 tumors, which were characterized by carcinomas in the upper third of the stomach, tumors larger than 5 cm, carcinomas of the ulcerating type, differentiated adenocarcinomas, tumors invading the subserosa, and those accompanied by lymph node metastasis or liver metastasis. The overestimated group had a significantly poorer prognosis than the correctly assessed cases (P < 0.05). Since multivariate logistic regression analysis showed that the significant risk factor related to the inaccurate intraoperative assessment of T stage was tumor size, the error in diagnosis may correlate with a greater degree of tumor spread. Surgeons should decide their therapeutic approach at the time of surgery on the basis of their intraoperative assessment of tumor spread. We recommend extensive surgery followed by adequate chemotherapy when serosal invasion is suspected at surgery.

Adenocarcinoma↗

The impact of positive peritoneal washings and serosal and adnexal involvement on survival in patients with stage IIIA uterine cancer.

OBJECTIVE: The aim of this study was to determine the prognostic significance of serosal involvement (SER), adnexal involvement (ADN), and positive peritoneal washings (PPW) in patients with Stage IIIA uterine cancer. We also sought to determine patterns of recurrence in patients with this disease. METHODS: The records of 136 patients with Stage IIIA uterine cancer treated at the Queensland Centre for Gynecological Cancer between March 1983 and August 2001 were reviewed. One hundred thirty-six patients underwent surgery and 58 (42.6%) had full surgical staging. Seventy-five patients (55.2%) had external beam radiotherapy and/or brachytherapy postoperatively. Overall survival was the primary statistical endpoint. Statistical analysis included univariate and multivariate Cox models. RESULTS: Forty-six patients (33.8%) had adnexal involvement, 23 (16.9%) had serosal involvement, and 40 (29.4%) had positive peritoneal washings. Median follow-up was 55.1 months (95% confidence interval, 36.9 to 73.4 months) after which time 71 patients (52.2%) remained alive. For patients with endometrioid adenocarcinoma, ADN and SER were associated with impaired survival on multivariate analysis (odds ratio 2.8 and 3.2, respectively). In the subgroup of patients with high-risk tumors (including papillary serous carcinomas, clear cell carcinomas, and uterine sarcomas), neither ADN, nor SER, nor PPW influenced survival. CONCLUSION: Patients with Stage IIIA uterine cancer constitute a heterogeneous group. For patients with endometrioid adenocarcinoma, both ADN and SER, but not PPW, were associated with impaired prognosis. For patients with high-risk histological types, prognosis is poor for all three factors.

Adult↗

Prophylaxis with intraoperative chemohyperthermia against peritoneal recurrence of serosal invasion-positive gastric cancer.

Continuous hyperthermic peritoneal perfusion (CHPP) with a solution which contains 30 mg mitomycin C and 300 mg cisplatin has been introduced as a prophylactic treatment for peritoneal recurrence after curative resection of 79 advanced gastric cancers. The control group consisted of 81 patients with advanced gastric cancer who underwent curative surgery during the same period. CHPP was performed for 60 minutes by perfusing MMC- and CDDP-containing saline solutions warmed at 43.5 degrees C by a special CHPP device. In patients with pathologically confirmed serosal invasion-positive tumors, the survival rate of the CHPP group was significantly higher than that of the control group. A survival advantage for stage IV patients was also obtained by CHPP. However, there was no survival advantage between the CHPP group and the control group with serosal invasion-negative tumors. Adverse effects were observed in four patients who underwent CHPP: One developed severe bone marrow suppression, and transient hyperazotemia was observed in the other three. There was no difference in the incidence of mortality and morbidity between the two groups. These results indicate that CHPP is a safe, readily available prophylactic therapy for peritoneal recurrence after gastric cancer surgery.

Antineoplastic Combined Chemotherapy Protocols↗

Mechanisms underlying the intestinal fluid secretion evoked by nociceptive serosal stimulation of the rat.

Intestinal net fluid transport was measured in vivo continuously with a gravimetric method. Chemical stimulation of the jejunal serosa with hydrochloric acid (0.1 M), ethanol (20%), cat bile or 7-deoxycholic acid (10 mM) evoked an intestinal fluid secretion. Hexamethonium (10 mg/kg b.wt.i.v.) or serosal application of lidocaine (1% solution) partially blocked this secretory response. Bradykinin and prostaglandin E1, two important inflammatory mediators, elicited fluid secretion when applied to the serosal surface at a concentration of 10(-4) M. This secretion was also partly inhibited by hexamethonium. Furthermore indomethacin (10 mg/kg b.wt. i.v.) or pyrilamine (10 mg/kg b.wt. i.v.), a H1-receptor blocker, partly inhibited the secretory response caused by chemical stimulation of the serosa while cimetidine (1 mg/kg b.wt. i.v.), a H2-receptor blocker, had no effect. Freeze sectioned samples from chemically stimulated intestines were examined by fluorescence microscopy. A leakage of i.v. administrated Evans blue labelled albumin into the interstitial space of the serosa and the outer layer of the muscularis was found. It is concluded: The intestinal fluid secretion studied is mainly elicited by nociceptive stimulation of nerves in the serosa or the outer muscularis. The reflex may be activated by the local release of histamine, kinins and prostaglandins. The reflex studied is part of an inflammatory response.

Animals↗

Angiographic diagnosis of the degree of serosal invasion of carcinoma of the colon.

Angiography using Prostaglandin E1 was performed on 38 patients with carcinoma of the colon in order to diagnose the degree of serosal cancer invasion. The findings at angiography were classified into four groups: 1) AG-S3, abnormal change (irregularity and/or encasement) up to marginal vessels; 2) AG-S2, abnormality up to vasa recta; 3) AG-S1, abnormality of penetrating branches of vasa recta within the wall of the colon; and 4) AG-S0, no distinct findings of above-mentioned vessels. These angiographic findings were compared with both macroscopic and microscopic serosal cancer invasion. Angiographic diagnosis is in accord with the macroscopic findings in 84.2 percent of cases. Angiographic diagnosis is in accord with the microscopic findings in 32.4 percent of cases. Macroscopic findings confirm the angiographic diagnosis precisely but the conflict with microscopic findings should not be overlooked. This may be the result of inflammatory change, adhesion, and fibrosis around carcinoma of the colon.

Adult↗

Evidence for a neurotensin receptor in rat serosal mast cells.

OBJECTIVE AND DESIGN: The ability of neurotensin (NT) at nmolar levels to stimulate exocytosis of the mast cell suggested that it could play a role in neuro-immune-endocrine interactions. The inhibition by a specific receptor antagonist of NT's mast cell stimulation suggested the presence of a specific mast cell NT receptor. We have here employed several probes to determine if a specific neurotensin receptor was present on rat serosal mast cells. MATERIAL: Serosal mast cells were isolated from the peritoneal and pleural cavities of male Sprague-Dawley rats. METHODS: Immunocytochemistry with an antibody raised against the C-terminal peptide of the neurotensin receptor was utilized. The same antibody was employed in immunoblotting following SDS gel electrophoresis of mast cell extracts. An RNA probe for ribonuclease protection assays (RPA) was prepared using the rat brain neurotensin receptor cDNA and polymerase chain reaction was carried out using primers based on the rat brain neurotensin receptor sequence. RESULTS: Mast cells showed specific staining with the anti-neurotensin receptor antibody and this same antibody revealed a protein on SDS gels migrating as a 70 kDa species. Ribonuclease protection assays revealed the predicted protected fragment at approximately 450 bp while PCR amplification gave a major product at 843 bp. CONCLUSIONS: These results indicate that a specific neurotensin receptor is present on the rat mast cell.

Animals↗

Evidence for P2Y-type ATP receptors on the serosal membrane of frog skin epithelium.

The present study presents the first evidence for P2Y-type adenosine 5'-triphosphate (ATP) receptors on the basolateral membranes of frog skin epithelial cells. Cytosolic calcium ([Ca2+]i) was measured with fura-2 and Calcium-Green-1 using epifluorescence microscopy and confocal laser scanning microscopy respectively. In the presence of Ca2+ in the solutions ATP increased [Ca2+]i. The increase in [Ca2+]i was due to the agonist activity of ATP and not to the activity of the potential products of ATP metabolism, i.e. adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) or adenosine, as shown by a comparison of the magnitude of the increases in [Ca2+]i caused by the various compounds. The rise in [Ca2+]i was predominantly monophasic at low ATP concentrations (below 100 microM). At higher concentrations the initial spike was followed by a plateau phase. In the absence of Ca2+ in the extracellular solution ATP caused Ca2+ release from intracellular stores. This could be inhibited by pre-treatment of the tissue with 1 microM thapsigargin, an inhibitor of the endoplasmic reticulum calcium ATPase. The nucleotide uridine 5'-triphosphate (UTP) had similar effects on [Ca2+]i although the plateau level of the [Ca2+]i response was higher with this P2Y agonist. Confocal laser scanning microscopy showed that all cell layers of the epithelium responded to ATP. Our data indicates that serosal ATP acts on serosal P2Y-type receptors in frog skin epithelium. This is the first evidence of a phospholipase C-coupled receptor in this tissue.

Adenosine Monophosphate↗

Serosal patch repair for benign duodenocolic fistula secondary to duodenal diverticulum.

A case of duodenocolic fistula secondary to a perforating diverticulum of the third portion of the duodenum was successfully managed by primary repair with use of a serosal patch over a difficult duodenal closure. The advantages of the serosal patch technic are discussed in light of other technics used for dealing with duodenal defects and fistulas.

Adult↗

Effects of secretagogues on the K+ permeability of mucosal and serosal borders of rabbit colonic mucosa.

(1) K+ efflux rates from the mucosal and serosal surfaces of sheets of rabbit colonic mucosa have been determined by measuring net K+ loss into K+-free Ringer solution bathing each side of the tissue. (2) Initially, there is a high rate of K+ loss from the tissue, this falls to a lower steady-state rate after 20 min. Loss of K+ from the tissue into the serosal bath is 6-8 fold faster than loss to the mucosal bath. (3) A number of intestinal secretagogues, e.g. theophylline, cyclic AMP, carbachol, ionophore A23187, as well as the laxative bisacodyl, raise the K+ efflux rate across the mucosal border by 200-300%. In the case of K+ efflux induced by carbachol the effect is shown to be dependent on raised levels of intracellular Ca2+. Ca2+-calmodulin complex does not appear to be be involved in activation of K+ efflux across the mucosal border. (4) Amiloride does not block mucosal K+ efflux, but tetraethyl-ammonium does inhibit K+ efflux across the mucosal border, induced by either bisacodyl or raised intracellular Ca2+. (5) The results suggest that laxatives may increase the rate of K+ secretion into the colonic lumen by raising the K+ permeability of the mucosal border.

Amiloride↗

Synthesis of a nitric oxide-like factor from L-arginine by rat serosal mast cells: stimulation of guanylate cyclase and inhibition of platelet aggregation.

Rat serosal mast cells were tested for their ability to generate a nitric oxide-like factor by two bioassay systems: inhibition of platelet aggregation and stimulation of mast cell guanylate cyclase. Incubation of rat serosal mast cells with human washed platelets resulted in an inhibition of thrombin-induced platelet aggregation proportional to the number of cells. The inhibition was potentiated by superoxide dismutase (SOD) and reversed by oxyhaemoglobin (oxyHb). The inhibitory activity of mast cells was also prevented by NG-monomethyl-L-arginine (MeArg), an effect reversed by co-incubation with L-Arg but not D-Arg. When mast cells alone were stirred at 1,000 rpm, a time-dependent increase in the levels of their cGMP but not cAMP was observed. This increase was reduced by pretreatment with MeArg. The inhibitory effect of MeArg was reversed by L-Arg but not D-Arg. These results demonstrate that rat mast cells release a factor with the same pharmacological profile as NO, and that this NO-like factor is derived from L-arginine.

Animals↗

The influence of serosal patch size on the growth of small intestinal neomucosa.

Several factors might affect the growth of neomucosa after serosal patching of small intestinal defects. Often only short segments of small intestine can be patched because of limited serosal surface and anatomic factors. The purpose of this study was to determine the influence of patch size on neomucosal growth. Twenty male New Zealand white rabbits underwent patching with colon serosa of either a 2 X 15-cm distal ileal defect (n = 10) or three 2 X 5-cm ileal defects (n = 10). There was significantly greater coverage of the patched defect by neomucosa in the triple patch group (99.4% vs 93.1% P less than 0.005) and significantly more of the smaller defects were completely covered by neomucosa than the larger defects (12 of 15 vs 0 of 5, P less than 0.05) at 8 weeks. The final area of the defect was 27.5 and 32.8% of the initial patched area respectively for the single and triple patches. Microscopically there was no difference in villous height or crypt depth, but crypt density was significantly greater in the triple group (207 +/- 11 vs 186 +/- 17 crypts/mm, P less than 0.05). In vitro glucose uptake and disaccharidase activity were similar in both groups. Patching multiple small intestinal defects results in more rapid neomucosal growth than a single large defect of the same surface area. This might be due to a greater circumference exposed to surrounding normal mucosa with a resultant increase in crypt density. Since function and villous development of the neomucosa are similar, multiple patches should result in a greater increase in absorptive capacity.

Animals↗

Determination of transepithelial (mucosal and serosal) electrical potentials in toad skin. Action of chemical agents.

1. Potential differences across the mucosal or outer, and the serosal or inner, membranes of the toad skin (M and S) were recorded separately. Total potential difference across the skin (T) and the short-circuit current (SCC) were recorded by means of the classical Ussing method. 2. The independent determination of the M and the S is of importance in the elucidation of the mechanism of action of agents which alter ion fluxes across the skin. 3. The percentage values of the M and the S obtained in toad skins during the summer were similar to the percentage values obtained by microelectrode impalement of cells. 4. Angiotensin II (AII) and antidiuretic hormone (ADH) increased T with a notable rise in M and a slight increase in S. These agents act mainly by increasing mucosal membrane permeability to Na+ since M is principally affected. 5. Amiloride and ouabain reversed M, decreased T and increased S above T. The reversal of M might be explained by the flow of a cation to the mucosal aspect or of an anion to the cell interior. 6. These results show that the effects of several agents on the toad skin potential may be analysed independently across the mucosal and serosal membranes and reflect the behaviour of the entire tissue rather than of a single cell.

Amiloride↗

Treatment results of endometrial carcinoma with positive peritoneal washing, adnexal involvement and serosal involvement.

AIMS: To review the treatment results of patients with endometrial carcinoma having positive peritoneal washing (PPW), adnexal involvement, uterine serosal involvement, or all three. MATERIALS AND METHODS: The treatment records of patients who had undergone primary surgery for endometrial cancer without distant metastasis during 1990--2001 at the Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, were reviewed. Thirty-five patients were found to have involvement of positive PPW, adnexal involvement, uterine serosal involvement, or all three. Seven (20%) of them had gross or microscopic lymph-node metastasis. Thirty-three (94.3%) patients received adjuvant radiotherapy (28 whole-pelvic irradiation [WPI]; five abdominal radiotherapy [WART]). Two patients with solitary ovarian metastasis received chemotherapy, and one with isolated PPW also received adjuvant hormonal therapy. The median follow-up was 50.4 months (range 2.4-151.2 months). Multivariate analysis was carried out using the Cox regression proportional hazards model. RESULTS: Among the 28 patients with clinical or pathological node-negative disease (International Federation of Gynecology and Obstetrics [FIGO] stage IIIA), only two patients with solitary ovarian metastases developed recurrence. The 5-year actuarial disease-free survival (DFS) rates for the whole group and patients without lymph-node involvement were 77.9% and 91.7%, respectively. Five out of the seven patients with lymph-node involvement developed recurrences. Univariate analysis showed that lymph-node involvement (P < 0.0001) and high-grade disease (P = 0.011) were the significant poor prognostic factors. Multivariate analysis showed that lymph-node involvement was the only significant poor prognostic factor to predict poor 5-year DFS (P = 0.0001). Only one patient (3.7%) who had received WART developed grade 4 toxicity. CONCLUSIONS: This study showed that good treatment results could be obtained from patients with stage IIIA endometrial carcinoma without clinical or pathological lymph-node involvement after adjuvant radiotherapy, with acceptable late side-effects. The relative prognostic importance of individual IIIA involvement and the optimal adjuvant treatment remain to be determined.

Adult↗

Role of plasminogen activators during healing after uterine serosal lesioning in the rat.

OBJECTIVE: Study the expression pattern of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activators during uterine serosal healing after lesioning in a rat model. DESIGN: Descriptive study with an adhesion model using reverse transcriptase-polymerase chain reaction (PCR) and immuncytochemical techniques. SETTING: Academic medical center. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Expression profiles of t-PA and u-PA were examined in the uteroperitoneal adhesion tissues of rat from the time of injury until day 7 after surgery using relative abundance reverse transcriptase-PCR and immunocytochemical techniques. RESULT(S): The t-PA transcript levels dropped in uteroperitoneal tissues by 6 hours after surgery and remained low until day 5. Thereafter, a rapid up-regulation of this transcript was observed at day 7. In contrast, the u-PA transcript levels demonstrated a biphasic profile during the progression of adhesion development with peaks at 2 and 5 days after surgery. Immunocytochemical staining demonstrated expression of these plasminogen activators in the newly formed blood vessels. CONCLUSION(S): Altered levels of t-PA and u-PA transcripts and its expression in newly formed blood vessels during healing and adhesion development indicate involvement of these plasminogen activators in serosal healing and adhesion development.

Animals↗

Effect of hemostatic agents in canine gastric serosal blood vessels.

The efficacy of various sclerotherapeutic agents in the control of acute bleeding, via subserosal injection, was assessed in 10 dogs. Blood flow rate (BFR) from severed gastric serosal vessels (diameter, 1.6 to 2.2 mm) was measured for 3 min (ml/min) for a control group and the agent used. The agents tested were 5 ml of normal saline (NS), 5 ml of 3% hypertonic saline (HS), 5 ml of 1:10,000 epinephrine in NS, 5 ml of 1:10,000 epinephrine/HS, 5 ml of 1:20,000 epinephrine/HS, 2 ml of old thrombin "cocktail" (thrombin, cephapirin + 1% tetradecyl), and 2 ml of fresh thrombin cocktail (total seven). One agent was tested per dog; there were one to two dogs in each subgroup. All of the agents showed significant reduction in BFR (except old thrombin) when compared with BFR of control vessels. The reduction ranged from 30% to more than 75% after 1:10 epinephrine/HS. Complete hemostasis was achieved in up to 47% of vessels using 1:20 epinephrine/HS. Overall, the epinephrine solutions achieved the best results. No systemic effects were observed with the use of any of the agents. Histological studies showed that epinephrine caused mild tissue damage, whereas the cocktail caused significant tissue necrosis. This serosal vessel model permits comparison of the effectiveness of each agent; however, clinical extrapolation to mucosal vessels in a patient and the long-term histological changes are not known.

Animals↗

Free serosal cells originating from the embryo of the wasp Diadromus pulchellus in the pupal body of parasitized leek-moth, Acrolepiosis assectella. Are these cells teratocyte-like?

In braconid species, teratocytes are derived from a serosal cell membrane which envelops the developing parasitoid embryo. On hatching, this membrane dissociates into individual cells, the teratocytes, which then circulate in the haemolymph of the host. We describe herein such a membrane, surrounding the embryo in eggs of the ichneumonid parasitoid wasp, Diadromus pulchellus. This membrane consisted of a single sheet of tightly packed cells with large 12+/-1.4 &mgr;m nuclei. These cells were released after hatching in vitro and cells of the same size were detected in vivo, in the vicinity of the D. pulchellus embryo. The number of nuclei detected suggests that the serosal membrane consists of about 450+/-150 cells. These cells did not grow after hatching of the parasitoid egg in the parasitized host, Acrolepiosis assectella, during the development of the parasitoid wasp larva. Southern blot experiments, using D. pulchellus satellite DNA or the ribosomal genes as probes, showed that free-living floating cells of wasp origin were present in the body of the parasitized host. This is the first time that free-floating teratocyte-like cells have been described in species of the Ichneumonidae.

Journal Article↗