Primary CD56+ NK/T-cell lymphoma of the rectum accompanied with refractory ulcerative colitis.

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.

Increased proliferation of middle to distal colonic cells during colorectal carcinogenesis in experimental murine ulcerative colitis.

Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. This association is widely attributed to colonic inflammation. However, the severity of colonic inflammation necessary for the development of dysplasia and/or cancer remains unknown. In this study, we investigated the pattern of cell proliferation in colorectal carcinogenesis in an experimental murine model of UC. Chronic colitis was induced by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% or 2% DSS for 7 days and then distilled water for 14 days). Mice were sacrificed after every cycle and at 120 days following the completion of the fourth cycle. Colonic cell proliferation was immunohistochemically evaluated using the thymidine analogue bromodeoxyuridine and the labeling index (LI) was determined. The incidence of dysplasia and/or cancer was 28%, 6.7%, and 0% in the 5% DSS, 2% DSS, and normal control groups respectively. All gross lesions were present in the middle to distal colon. Disease activity index and total LI after four cycles of DSS were significantly higher in the 5% DSS group compared to the 2% DSS group. In the 5% DSS group, the LI was significantly higher in the middle colon than in the proximal colon. Simple repeated administration of the non-genotoxic colon carcinogen DSS induced dysplasia and/or cancer. In addition, we have demonstrated the presence of regional differences in proliferation pattern between the middle and the proximal colon during carcinogenesis in experimental murine UC. These findings may provide insight into the development of colorectal cancer in humans with long-standing UC.

Epidermal growth factor receptor is a possible predictor of sensitivity to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma.

BACKGROUND: Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. METHODS: We reviewed 62 patients with T(3-4), N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. RESULTS: The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. CONCLUSION: Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.

Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. Cyclooxygenase (COX)-2 inhibitors are known to suppress sporadic colorectal cancer, but it is unknown whether selective COX-2 inhibitors exhibit a preventive effect in UC-associated neoplasia. This study investigated the preventive effect of nimesulide, a selective COX-2 inhibitor, on colorectal carcinogenesis in an experimental model of murine UC. METHODS: Chronic colitis was induced in mice by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% DSS for 7 days and then distilled water for 14 days). The mice were killed 120 days after the completion of the fourth cycle. The mice were divided into the following five groups: group A served as a disease control; group B received a diet mixed with 400 p.p.m. of nimesulide during the whole period; group C received nimesulide during the four cycles of DSS administration (active phase); group D received nimesulide for 120 days from the end of the fourth cycle (remission phase); group E received no agents including DSS and served as a normal control. RESULTS: The incidence of dysplasia and/or cancer was 28%, 15%, 11.8%, 6.7% and 0% in groups A-E, respectively. In group D, nimesulide significantly suppressed the occurrence of dysplasia and/or cancer (P < 0.05). Strong COX-2 expression was detected by immunohistochemistry in cancer and dysplastic lesions while diffusely weak COX-2 expression was also found in the residual colon (i.e. lesion-free colon). The mucosal concentration of prostaglandin E(2) was significantly lower in groups B and D than in group A. CONCLUSIONS: The administration of the selective COX-2 inhibitor nimesulide (especially during the remission phase) exerts a suppressive effect on the development of dysplasia and/or cancer in a murine model of DSS-induced colitis. These findings may have relevance to long-standing UC in humans.

Evaluation of prognostic factors of esophageal squamous cell carcinoma (stage II-III) after concurrent chemoradiotherapy using biopsy specimens.

BACKGROUND: Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. METHODS: The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. RESULTS: The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. CONCLUSIONS: PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT.

[Cl-]i modulation of Ca2+-regulated exocytosis in ACh-stimulated antral mucous cells of guinea pig.

The effects of intracellular Cl- concentration ([Cl-]i) on acetylcholine (ACh)-stimulated exocytosis were studied in guinea pig antral mucous cells by video microscopy. ACh activated Ca2+-regulated exocytosis (an initial phase followed by a sustained phase). Bumetanide (20 microM) or a Cl- -free (NO3-) solution enhanced it; in contrast, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, a Cl- channel blocker) decreased it and eliminated the enhancement induced by bumetanide or NO3- solution. ACh and Ca2+ dose-response studies demonstrated that NO3- solution does not shift their dose-response curves, and ATP depletion studies by dinitrophenol or anoxia demonstrated that exposure of NO3- solution prior to ATP depletion induced an enhanced initial phase followed by a sustained phase, whereas exposure of NO3- solution after ATP depletion induced only a sustained phase. Intracellular Ca2+ concentration ([Ca2+]i) measurements showed that bumetanide and NO3- solution enhanced the ACh-stimulated [Ca2+]i increase. Measurements of [Cl-]i revealed that ACh decreases [Cl-]i and that bumetanide and NO3- solution decreased [Cl-]i and enhanced the ACh-evoked [Cl-]i decrease; in contrast, NPPB increased [Cl-]i and inhibited the [Cl-]i decrease induced by ACh, bumetanide, or NO3- solution. These suggest that [Cl-]i modulates [Ca2+]i increase and ATP-dependent priming. In conclusion, a decrease in [Cl-]i accelerates ATP-dependent priming and [Ca2+]i increase, which enhance Ca2+-regulated exocytosis in ACh-stimulated antral mucous cells.

HLA genotype and development of gastric cancer in patients with Helicobacter pylori infection.

BACKGROUND/AIMS: Helicobacter pylori (HP) infection is reported to be involved in gastric carcinogenesis. However, only a small percentage of HP-infected patients actually develop gastric cancer. In the present study, we assessed HLA antigen polymorphism and investigated its relationship with the development of gastric epithelial tumors in patients who had HP infection. METHODOLOGY: Among patients with serologically proven HP infection, 80 cases who underwent endoscopic mucosectomy for gastric epithelial tumors (24 adenomas and 56 carcinomas) were recruited in the study (the tumor group), and 20 cases without tumors were also included as controls (the nontumor group). HLA status (HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1) was determined by HLA-DNA typing. RESULTS: HLA-B*05401, HLA-DQB1*0601 and HLA-DRB1*1502 genes showed a significantly higher frequency in the control group than in the tumor group (0.225 vs. 0.088, P=0.015; 0.3 vs. 0.163, P = 0.047; 0.175 vs. 0.069, P = 0.036, respectively). CONCLUSIONS: It suggests that HLA-B*5401, HLA-DQB1*0601 and HLA-DRB1*1502 may contribute to the inhibition of gastric carcinogenesis. Thus, HP-infected patients without these genotypes should undergo HP eradication therapy and close follow-up.

Evaluation of the effect of pyrrolidine dithiocarbamate in suppressing inflammation in mice with dextran sodium sulfate-induced colitis.

AIM: To evaluate the effect of pyrrolidine dithio-carbamate (PDTC; an NF-kappaB inhibitor) administered at low (50 mg/kg) and high (100 mg/kg) doses in suppressing colitis in mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice were divided into a DSS-untreated group (normal group), DSS-treated control group, DSS+PDTC-treated group I (low-dose group), and DSS+PDTC-treated group II (high-dose group). In each group, the disease activity index score (DAI score), intestinal length, histological score, and the levels of activated NF-kappaB and inflammatory cytokines (IL-1beta and TNF-alpha) in tissue were measured. RESULTS: The DSS+PDTC-treated group II exhibited suppression of shortening of intestinal length and reduction of DAI score. Activated NF-kappaB level and IL-1beta and TNF-alpha levels were significantly lower in DSS+PDTC-treated group II. CONCLUSION: These findings suggest that PDTC is useful for the treatment of ulcerative colitis.

Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer.

PURPOSE: To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. MATERIALS AND METHODS: TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. RESULTS: In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. CONCLUSION: This study suggests that, via down-regulation of TS by irinotecan treatment, combination chemotherapy with S-1 and irinotecan could be effective in gastric cancer patients with high TS levels.

How closely is Helicobacter pylori infection related to gastroduodenal lesions?

BACKGROUND/AIMS: Various studies have indicated a relationship between Helicobacter pylori infection and upper gastrointestinal lesions, but this relationship needs to be assessed in individuals not seeking medical treatment for complaints. METHODOLOGY: We screened community residents for H. pylori infection and upper gastrointestinal lesions during an annual mass health examination aiming to determine relationships between infection and lesions. In 932 examinees we performed a 13C-urea breath test for H. pylori infection, and assessed degree of gastric atrophy by measuring pepsinogen I and II in serum. In 738 subjects we also performed upper gastrointestinal radiography with or without endoscopy. RESULTS: Prevalence of H. pylori infection increased with age, and the ratio of serum pepsinogen I to II decreased with age. Prevalence of H. pylori infection did not differ significantly between subjects with and without radiographically or endoscopically evident lesions. Of H. pylori-positive subjects with peptic ulcer, 73.2% had no recurrence of ulcer despite absence of medical treatment. CONCLUSIONS: Prolonged H. pylori infection was associated with atrophy of the gastric mucosa, but little relationship was evident between H. pylori infection and development or recurrence of peptic ulcer.

Prostaglandin E2 release in gastric antral mucosa of guinea-pigs: basal PGE2 release by cyclo-oxygenase 2 and ACh-stimulated PGE2 release by cyclo-oxygenase 1.

Prostaglandin E(2) (PGE(2)), which is generated by two isoforms of cyclo-oxygenase (COX(1) and COX(2)), is a key mediator in gastric mucosal defense. In the present study, antral mucosa of guinea-pigs was incubated with various agonists or antagonists in a medium, the PGE(2) concentration of which was measured using a PGE(2) EIA kit. Prostaglandin E(2) was released from the antral mucosa spontaneously (basal PGE(2) release) and acetylcholine (ACh, 10 microM) enhanced the PGE(2) release (ACh-stimulated PGE(2) release) was mediated via intracellular Ca(2+) concentration ([Ca(2+)](i)). Arachidonic acid enhanced both forms of PGE(2) release, and a phospholipase A(2) inhibitor (amylcinnamoyl anthranilic acid) and COX inhibitors (acetylsalicylic acid and indomethacin) decreased them. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazol (SC560, 100 nm, a COX(1)-selective inhibitor) inhibited ACh-stimulated PGE(2) release without any decrease in basal PGE(2) release. N-(2-Cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS398, 20 microM, a COX(2)-selective inhibitor) decreased basal PGE(2) release without any reduction of ACh-stimulated PGE(2) release. However, ionomycin (a Ca(2+) ionophore) increased PGE(2) release from antral mucosa in the presence of SC560 or NS398, suggesting that COX(1) and COX(2) are regulated by [Ca(2+)](i). These findings indicate that COX(1)-containing cells have ACh receptors but COX(2)-containing cells do not. Moreover, in isolated antral epithelial cells, SC560 decreased basal and ACh-stimulated PGE(2) release, but NS398 did not. In conclusion, in antral mucosa, basal PGE(2) release is mainly maintained by COX(2) of non-epithelial cells, and ACh-stimulated PGE(2) release is maintained by COX(1) of epithelial cells.

[Weekly administration regimen of paclitaxel (PTX) in patient with inoperable or recurrent gastric cancer].

Paclitaxel is one of the new drugs against advanced/recurrent gastric cancer. We report its efficacy and toxicity with weekly administration for advanced/recurrent gastric cancer. We administered 26 patients (postoperative/non-operation=9/17) PTX 80 mg/m(2)by 1-hour intravenous infusion once a week for 3 weeks followed by one week rest. Median PTX administrations were 2.0 cycles (range:1-22). Characteristics of the patients were median age of 62 (range: 37-78) and PS 0/1/2:2/17/7, male/female:18/8. Over grade 3 toxicities did not occur. The overall response rate was 14.3%, and the non-PD rate was 66.8%. Median time to treatment failure was 61 days and median survival time was 221 days. These results suggest that weekly PTX has modest activity with a favorable toxicity profile in patients with advanced/recurrent gastric cancer, and so this regimen may thus might be recommended in an outpatient treatment setting.

[A case of gastric cancer with multiple liver metastases resistant to TS-1 responding to chemotherapy with paclitaxel plus doxifluridine].

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

Expression of gamma-aminobutyric acid and glutamic acid decarboxylases in rat descending colon and their relation to epithelial differentiation.

OBJECTIVE: To detect the expression of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylases (GADs; including two isoforms GAD65 and GAD67) in the epithelial growth zones of the descending colon in rats, and to investigate their relation to epithelial differentiation and proliferation. METHODS: The expression of GABA and GADs in rat descending colon was investigated by immunofluorescent staining and confocal laser scanning techniques, and goblet cells were further investigated by wheat-germ agglutinin histochemistry. In addition, GAD65 and GAD67 mRNAs were also detected by reverse transcription-polymerase chain reaction. Furthermore, evaluation of cell kinetics in colonic epithelia was conducted by ABC immunostaining using a monoclonal antibody against proliferating cell nuclear antigen (PCNA). RESULTS: Immunoreactive GABA and GADs were distributed in the upper third of the crypts and at the luminal surface in the rat descending colon. Strong staining for GABA and GADs was localized mainly in the cytoplasm of epithelial cells near the neck of the crypts and along the luminal surface. In addition, GABA and GAD65 were also detected at the lamina propria in colonic mucosa. No staining for GABA or GADs was found in goblet cells. GAD65 and GAD67 mRNAs were identified in homogenates of rat descending colon. PCNA labeled nuclei were found in the lower two-thirds of the crypts. CONCLUSIONS: The expression of GABA and GADs in the maturation and function zones of rat descending colon suggests that GABA may be involved in the differentiation of colonic epithelial cells.

[Principles of managing chemotherapy-induced nausea and vomiting].

Chemotherapy-induced nausea and vomiting (emesis) can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. For patients treated with emetogenic chemotherapy, it is very important to prevent nausea and vomiting completely. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by numerous factors, including: 1) the specific chemotherapeutic agents used; 2) their dosage; 3) the schedule and route of administration; and 4) individual patient variability. Approximately 70 to 80% of all cancer patients receiving chemotherapy experience emesis, whereas 10% to 44% experience anticipatory emesis. The following general principles are recommended. 1) A 5-HT3 receptor antagonist should be administered prior to each day's 1st dose of moderately or highly emetogenic chemotherapy. 2) Dexamethasone should be administered once daily either orally or intravenously for every day of moderately or highly-emetogenic chemotherapy and for 2-3 days after chemotherapy for regimens that are likely to cause significant delayed-emesis. 3) The most effective way to treat anticipatory nausea and/or vomiting is to prevent it by using optimal antiemetic therapy during every cycle of treatment.

cGMP modulation of ACh-stimulated exocytosis in guinea pig antral mucous cells.

In guinea pig antral mucous cells, ACh stimulates the Ca(2+)-regulated exocytosis, which has a characteristics feature: an initial transient phase followed by a sustained phase. The effects of cGMP on ACh-stimulated exocytosis were studied in guinea pig antral mucous cells using video microscopy. cGMP enhanced the frequency of ACh-stimulated exocytotic events, whereas cGMP alone did not induce any exocytotic events under the ACh-unstimulated condition. cGMP did not stimulate either Ca(2+) mobilization or cAMP accumulation. The Ca(2+) dose-response studies demonstrated that cGMP shifted the dose-response curve upward with no shift to the lower concentration. This indicates that cGMP increased maximal responsiveness of the Ca(2+)-regulated exocytosis, but not the Ca(2+) sensitivity. Moreover, under a condition of ATP depletion by dinitrophenol (DNP) or anoxia (N(2) bubbling), ACh evoked only a sustained phase in exocytotic events with no initial transient phase. However, ACh evoked an initial transient phase followed by a sustained phase with addition of cGMP before ATP depletion, whereas only a sustained phase was evoked in a case of cGMP addition after ATP depletion. Thus cGMP-induced enhancement in ACh-stimulated exocytotic events requires ATP, suggesting that cGMP modulates ATP-dependent priming of Ca(2+)-regulated exocytosis in antral mucous cells. In conclusion, cGMP increases the number of primed granules via acceleration of the ATP-dependent priming, which enhances the Ca(2+)-regulated exocytosis stimulated by ACh.

Enhancement of Ca2+-regulated exocytosis by indomethacin in guinea-pig antral mucous cells: arachidonic acid accumulation.

Ca2+-regulated exocytosis is enhanced by an autocrine mechanism via the PGE2-cAMP pathway in antral mucous cells of guinea-pigs. The inhibition of the PGE2-cAMP pathway by H-89 (an inhibitor of protein kinase A, PKA) or aspirin (ASA, an inhibitor of cyclo-oxygenase, COX) decreased the frequency of ACh-stimulated exocytotic events by 60%. Indomethacin (IDM, an inhibitor of COX), however, decreased the frequency of ACh-stimulated exocytotic events only by 30%. Moreover, IDM increased the frequency of ACh-stimulated exocytotic events by 50% in H-89-treated or ASA-treated cells. IDM inhibits the synthesis of Prostaglandin (PGG/H) and (15R)-15-hydroxy-5,8,11 cis-13-trans-eicosatetraenoic acid (15R-HPETE), while ASA inhibits only the synthesis of PGG/H. Thus, IDM may accumulate arachidonic acid (AA). AACOCF3 or N-(p-amylcinnamoyl) anthranilic acid (ACA; both inhibitors of phospholipase A2, PLA2), which inhibits AA synthesis, decreased the frequency of ACh-stimulated exocytotic events by 60%. IDM, however, did not increase the frequency in AACOCF3-treated cells. AA increased the frequency of ACh-stimulated exocytotic events in AACOCF3- or ASA-treated cells, similar to IDM in ASA- and H-89-treated cells. Moreover, in the presence of AA, IDM did not increase the frequency of ACh-stimulated exocytotic events in ASA-treated cells. The PGE2 release from antral mucosa indicates that inhibition of PLA2 by ACA inhibits the AA accumulation in unstimulated and ACh-stimulated antral mucosa. The dose-response study of AA and IDM demonstrated that the concentration of intracellular AA accumulated by IDM is less than 100 nm. In conclusion, IDM modulates the ACh-stimulated exocytosis via AA accumulation in antral mucous cells.

Phase I study of S-1 combined with irinotecan (CPT-11) in patients with advanced gastric cancer (OGSG 0002).

OBJECTIVE: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer. METHODS: S-1 was administered orally at 80 mg/m(2)/day for 21 consecutive days followed by a 2 week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 40 mg/m(2)/day, stepping up to 60, 80, 100 or 120 mg/m(2)/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study. RESULTS: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m(2), because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m(2). The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15. CONCLUSIONS: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.

Refractory ulcerative colitis accompanied with cytomegalovirus colitis and multiple liver abscesses: a case report.

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (UC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.

Inhibition of ACh-stimulated exocytosis by NSAIDs in guinea pig antral mucous cells: autocrine regulation of mucin secretion by PGE2.

The effects of indomethacin (IDM) and aspirin (ASA) on ACh (10 microM) -stimulated exocytotic events were studied in guinea pig antral mucous cells by using video optical microscopy. IDM or ASA, which inhibits cyclooxygenase (COX), decreased the frequency of ACh-stimulated exocytotic events by 30% or 60%, respectively. The extent of inhibition induced by ASA (60%) decreased by 30% when IDM or arachidonic acid (AA, the substrate of COX) was added. IDM, unlike ASA, appears to induce the accumulation of AA, which enhances the frequency of ACh-stimulated exocytotic events in ASA-treated cells. ONO-8713 (100 microM; an inhibitor of the EP1-EP4 prostaglandin receptors) and N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, HCl (H-89, 20 microM; an inhibitor of PKA) also decreased the frequency of ACh-stimulated exocytotic events by 60%. However, the supplementation of PGE(2) (1 microM) prevented the IDM-induced decrease in the frequency of ACh-stimulated exocytotic events. SC-560 (an inhibitor of COX-1) decreased the frequency of ACh-stimulated exocytotic events by 30%, but NS-398 (an inhibitor of COX-2) did not. Moreover, IDM decreased the frequency of exocytotic events stimulated by ionomycin, suggesting that COX-1 activity is stimulated by an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). ACh and ionomycin increased PGE(2) release in antral mucosal cells. In conclusion, in ACh-stimulated antral mucous cells, an increase in [Ca(2+)](i) activates Ca(2+)-regulated exocytotic events and PGE(2) release mediated by COX-1. The released PGE(2) induces the accumulation of cAMP, which enhances the Ca(2+)-regulated exocytosis. The autocrine mechanism mediated by PGE(2) maintains the high-level mucin release from antral mucous cells during ACh stimulation.