Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4 + cells recruited from bone marrow.

BACKGROUND: Angiogenesis is essential for gastric ulcer healing. Recent results suggest that vascular endothelial growth factor receptor 1 (VEGFR1), which binds to VEGF, promotes angiogenesis. In the present study, we investigated the role of VEGFR1 signaling in gastric ulcer healing and angiogenesis. METHODS: Gastric ulcers were induced by serosal application of 100 % acetic acid in wild-type (WT) and tyrosine kinase-deficient VEGFR1 mice (VEGFR1 TK(-/-)). Bone marrow transplantation into irradiated WT mice was carried out using bone marrow cells isolated from WT and VEGFR1 TK(-/-) mice. RESULTS: Ulcer healing was delayed in VEGFR1 TK(-/-) mice compared to WT mice and this was accompanied by decreased angiogenesis, as evidenced by reduced mRNA levels of CD31 and decreased microvessel density. Recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) was suppressed and epidermal growth factor (EGF) expression in ulcer granulation tissue was attenuated. Treatment of WT mice with neutralizing antibodies against VEGF or CXCR4 also delayed ulcer healing. In WT mice transplanted with bone marrow cells from VEGFR1 TK(-/-) mice, ulcer healing and angiogenesis were suppressed, and this was associated with reduced recruitment of bone marrow cells to ulcer granulation tissue. VEGFR1 TK(-/-) bone marrow chimeras also exhibited downregulation of EGF expression on CXCR4(+)VEGFR1(+) cells recruited from the bone marrow into ulcer lesions. CONCLUSION: VEGFR1-mediated signaling plays a critical role in gastric ulcer healing and angiogenesis through enhanced EGF expression on VEGFR1(+)CXCR4(+) cells recruited from the bone marrow into ulcer granulation tissue.

NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4(+)VEGFR1(+) cells to the ulcer granulation tissues.

BACKGROUND: Ulcer healing is a complex process, which involves cell migration, proliferation, angiogenesis and re-epithelialization. Several growth factors have been implicated in this process but the precise mechanism is not well understood. This study examined the involvement of VEGFR1 signaling in the gastric ulcer healing. METHODS: Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. RESULTS: The healing of acetic acid induced ulcers and the progenitor cells expressing CXCR4(+)VEGFR1(+) cell were significantly delayed in NSAID treated mice. The areas of the ulcer was significantly suppressed in tyrosine kinase-deficient VEGFR1 mice (VEGFR1TKKO) compared with wild type (WT) mice. The plasma level of SDF-1 and stem cell factor (SCF) and bone marrow level of pro-matrix metallopeptidase 9 (pro-MMP-9) were significantly reduced in VEGFR1TKKO mice. In VEGFR1 TKKOmice, the progenitor cells expressing CXCR4(+)VEGFR1(+) cell from bone marrow and the recruitment of these cells in healing ulcer were suppressed. Furthermore, VEGFR1 TKKO mice treated with NSAID did not suppress gastric ulcer healing compared to vehicle mice. These results suggested that NSAID suppressed VEGFR1 TK signaling plays a critical role in ulcer healing through mobilization of CXCR4(+)VEGFR1(+) cells. CONCLUSION: VEGFR1 signaling is required for healing of NSAID induced gastric ulcer and angiogenesis with increased recruitment of CXCR4(+)VEGFR1(+) cells to the ulcerative lesion.

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601).

PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer. METHODS: Docetaxel (40 mg/m(2)) and cisplatin (70 or 60 mg/m(2)) were given on day 1 of a 28-day cycle. S-1 (40 mg/m(2)) was given twice daily on days 1-14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1. RESULTS: Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1-25). Because some patients had serious myelosuppression and renal dysfunction with 70 mg/m(2) of cisplatin, dose of cisplatin was reduced to 60 mg/m(2) after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71-91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6-21.5) and 8.7 (95% CI, 6.7-10.7) months, respectively. CONCLUSIONS: Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60 mg/m(2) of cisplatin is as effective as 70 mg/m(2) of cisplatin.

Thromboxane A(2) receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment.

It is thought that thromboxane A(2) (TxA(2)) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA(2) is involved in liver repair. The objective of the present study was to examine the role of TxA(2) receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl(4)) was used to induce liver injury in TP knockout (TP(-/-)) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48h, respectively, and then declined. In TP(-/-) mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP(-/-) mice, the accumulation of hepatic CD11b(+)/F4/80(+) macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C-C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl(4)-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression.

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers.

The importance of prostaglandin E(2) in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-ß, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

Fulminant amoebic colitis during chemotherapy for advanced gastric cancer.

A 52-year-old man had bloody stools during chemotherapy for gastric cancer. A colonoscopy revealed necrotizing ulcer-like changes. A biopsy confirmed the presence of amoebic trophozoites. Subsequently, peritonitis with intestinal perforation developed, and emergency peritoneal lavage and colostomy were performed. After surgery, endotoxin adsorption therapy was performed and metronidazole was given. Symptoms of peritonitis and colonitis resolved. However, the patient's general condition worsened with the progression of gastric cancer. The patient died 50 d after surgery. Fulminant amoebic colitis is very rarely associated with chemotherapy. Amoebic colitis should be considered in the differential diagnosis of patients who have bloody stools during chemotherapy.

Clinical outcomes of endoscopic oblique aspiration mucosectomy for superficial esophageal cancer.

BACKGROUND: EMR is now a widely accepted option for the treatment for superficial esophageal cancer (SEC). However, studies of medium-term to long-term outcomes are scarce. OBJECTIVE: To evaluate outcomes in patients with SEC who are undergoing medium-term to long-term follow-up after endoscopic oblique aspiration mucosectomy (EOAM). DESIGN: A single-center retrospective study. SETTING: Kitasato University East Hospital, Sagamihara, Kanagawa, Japan. PATIENTS AND INTERVENTIONS: From November 1999 to October 2005, 85 patients with SEC underwent EOAM. All tumors were macroscopically classified as the superficial type on the basis of preoperative endoscopic and EUS findings. Patients were followed-up, with an endoscopy every 6 months. MAIN OUTCOME MEASUREMENTS: Therapeutic efficacy, complications, and follow-up results. RESULTS: The rate of complete resection was 82.5% (70/85). In patients who underwent an incomplete resection, argon plasma coagulation and heat probe coagulation were, in addition, performed. The median longest diameter of the resected specimens was 25 mm. The median time required for a resection was 27 minutes. There was no perforation. Bleeding after an EOAM occurred in 1 patient (1.2%). Esophageal stenosis developed in 8 patients (9.4%). All strictures were managed by endoscopic balloon dilation, and symptoms improved. The median follow-up period after EMR was 36 months (range 6-72 months). Local recurrence occurred in 5 patients (5.9%); the nonrecurrence rate was 96.4% at 1 year, 95.0% at 2 years, and 93.4% at 3 years. As additional treatment, argon plasma coagulation was performed in 4 patients, and endoscopic mucosal dissection was conducted in 1 patient. CONCLUSIONS: EOAM is a safe, easy, and effective procedure for the treatment of SEC that can be completed within a short time. The rate of local recurrence is low on medium-term to long-term follow-up.

[Therapeutic strategy for type 4 gastric cancer from the clinical oncologist standpoint].

Type 4 gastric cancer has a poor prognosis compared with other types of advanced gastric cancer because of the high incidence of peritoneal metastasis which causes intestinal obstruction, hydronephrosis, or obstructive jaundice. Surgical treatment is often only palliative, and systematic chemotherapy is considered to be important for long survival. S-1 showed a higher response rate for undifferentiated-type adenocarcinoma, and S-1 alone or its combination regimens demonstrated greater anti-tumor effects and longer survival time for gastric linitis plastica compared with conventional 5-FU regimens in our historical control study (response rate: S-1/non S-1 57.9%/27.9%, p<0.01; MST: S-1/non S-1 402 days/213 days, p<0.01). S-1 regimens may also improve the survival in patients with type 4 gastric cancer in neoadjuvant or adjuvant settings, but further prospective studies are warranted to prove its significance. Paclitaxel also has a high response rate for undifferentiated-type adenocarcinoma, and can be expected to show high efficacy for peritoneal dissemination. Irinotecan should not be administered in case of intestinal obstruction because its toxicity may be increased. However,survival of patients with type 4 gastric cancer may improve with the availability of active agents like S-1, taxanes, irinotecan as reported in colorectal cancer. Therefore,irinotecan should be administered carefully before intestinal obstruction occurs.

BCL-6-positive human herpesvirus 8-associated solid lymphoma arising from liver and spleen as multiple nodular lesions.

We report a case of BCL-6-positive B cell lymphoma with human herpesvirus 8 (HHV-8) infection. A human immunodeficiency virus-infected patient developed a diffuse large B cell lymphoma, which was found exclusively in the liver and spleen with the absence of lymphadenopathy and effusion in any body cavities. The lymphoma cells were composed of medium to large-sized cells positive for CD20, CD45, and BCL-6, and negative for epithelial cell membrane antigen, CD30, CD45RO, and CD138/syndecan-1, suggesting a germinal center B cell origin. The patient was serologically positive for HHV-8, and HHV-8 was detected in the liver biopsy tissue both by polymerase chain reaction and by immunohistochemistry for HHV-8-encoded latency-associated nuclear antigen. Other HHV-8-associated diseases, such as Kaposi's sarcoma, primary effusion lymphoma, or multicentric Castleman's disease were not detected in the patient. Chemotherapy was effective and reduced the size of the lymphoma dramatically. This is the first case report of a germinal center B cell-originating lymphoma with HHV-8 infection.