Two Cases of Atraumatic Chylous Ascites Characterized by Hypotriglyceridemia and Partially Managed with an Oral Fat-Free Elemental Diet.

Most cases of chylous ascites occur after surgery, but it also develops in nonoperative cases, although rarely. Such cases are often difficult to treat. In this study, we treated 2 cases of atraumatic chylous ascites, which were controlled by combining diuretic treatment with an oral fat-free elemental diet (Elental®, EA Pharma Co., Ltd., Tokyo, Japan). Elental can provide oral nutrition compatible with a lipid-restricted diet, which may be useful for control of chylous ascites. We report on these cases, including literature review-based considerations.

A case of large cell neuroendocrine carcinoma of the stomach with multiple liver metastases.

A 79-year-old man was admitted to our hospital to determine the cause of his melena. He underwent esophagogastric endoscopy and computed tomography, revealing a submucosal tumor on the anterior wall of the gastric antrum with multiple liver metastases. Endoscopic biopsy revealed a large cell neuroendocrine cell carcinoma. A subtotal gastrostomy was performed to prevent pyloric stenosis and anemia caused by tumor hemorrhage. Previous studies on gastric neuroendocrine carcinoma reported poor prognosis. Large- and small-cell types of gastric neuroendocrine carcinomas were differentiated for the first time in the 14th edition of the Japanese Classification of Gastric Carcinoma. It is expected that the number of reports of gastric neuroendocrine carcinomas classified as either the large-cell or small-cell type will increase. It is necessary to collect information on more cases to improve prognosis and to establish appropriate treatment guidelines.

Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer.

Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer.

Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model.

Recent studies have revealed that platelet-derived growth factor (PDGF) plays a role in promoting progressive tumor growth in several organs; however, whether PDGF plays such a role in gastric carcinoma is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis in an orthotopic nude mouse model of human gastric carcinoma. TMK-1 human gastric carcinoma cells were injected into the gastric wall of nude mice. Groups of mice (n = 10 each) received sterile water (control), low-dose imatinib (50 mg/kg/day), high-dose imatinib (200 mg/kg/day), cancer chemotherapeutic agent irinotecan (5 mg/kg/week), or imatinib (50 mg/kg/day or 200 mg/kg/day) and irinotecan (5 mg/kg/week) in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically. Carcinoma-associated fibroblasts, pericytes and lymphatic endothelial cells in stroma expressed high levels of PDGF-R; carcinoma cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastases. Immunohistochemically, only imatinib alone or in combination with irinotecan was shown to significantly decrease the stromal reaction, microvessel area and pericyte coverage of tumor microvessels. These effects were marked with high-dose imatinib. In conclusion, administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric carcinoma by blockade of PDGF-R signaling pathways in stromal cells.

Potential role for vascular endothelial growth factor-D as an autocrine factor for human gastric carcinoma cells.

Vascular endothelial growth factor (VEGF)-D induces lymphangiogenesis by activating VEGF receptor (VEGFR)-3, which is expressed mainly by lymphatic endothelial cells. VEGFR-3 has also been detected in several types of malignant cells, but the significance of VEGFR-3 expression by malignant cells remains unclear. We examined the expression and function of VEGF-D/VEGFR-3 in human gastric carcinoma cells. Expression of VEGF-D and VEGFR-3 was analyzed in three human gastric carcinoma cell lines and 29 surgical specimens. cDNA microarray analysis was used to examine the effect of VEGF-D on the expression of genes associated with disease progression in VEGFR-3-expressing KKLS cells. VEGF-D-transfected cells and control cells were transplanted into the gastric wall of nude mice. In 10 of the 29 (34%) gastric carcinoma specimens and two of the three cell lines, cancer cells expressed both VEGF-D and VEGFR-3. In vitro treatment of KKLS cells with exogenous VEGF-D increased expression of cyclin D1 and Bcl-2 and stimulated cell proliferation. VEGF-D transfection into KKLS cells resulted in stimulation of angiogenesis, lymphangiogenesis, and cell proliferation, and in inhibition of apoptosis. VEGF-D may participate in the progression of human gastric carcinoma by acting via autocrine and paracrine mechanisms.

Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor ß is associated with lymphatic metastasis in human gastric carcinoma.

Recent study of murine fibrosarcoma has revealed that platelet-derived growth factor (PDGF) plays a direct role in promoting lymphangiogenesis and metastatic spread to lymph nodes. Thus, we investigated the relation between PDGF and PDGF receptor (PDGF-R) expression and lymphatic metastasis in human gastric carcinoma. We examined PDGF-B and PDGF-Rß expression in four human gastric carcinoma cell lines (TMK-1, MKN-1, MKN-45, and KKLS) and in 38 surgical specimens of gastric carcinoma. PDGF-B and PDGF-Rß expression was examined by immunofluorescence in surgical specimens and in human gastric carcinoma cells (TMK-1) implanted orthotopically in nude mice. Groups of mice (n = 10, each) received saline (control) or PDGF-R tyrosine kinase inhibitor imatinib. PDGF-B and PDGF-Rß mRNA expression was significantly higher in patients with lymph node metastasis than in those without and was also significantly higher in diffuse-type carcinoma than in intestinal-type carcinoma. In surgical specimens, tumor cells expressed PDGF-B, but PDGF-Rß was expressed predominantly by stromal cells. Under culture conditions, expression of PDGF-B mRNA was found in all of the gastric cell lines, albeit at different levels. In orthotopic TMK-1 tumors, cancer cells expressed PDGF-B but not PDGF-Rß. PDGF-Rß was expressed by stromal cells, including lymphatic endothelial cells. Four weeks of treatment with imatinib significantly decreased the area of lymphatic vessels. Our data indicate that secretion of PDGF-B by gastric carcinoma cells and expression of PDGF-Rß by tumor-associated stromal cells are associated with lymphatic metastasis. Blockade of PDGF-R signaling pathways may inhibit lymph node metastasis of gastric carcinoma.

Mesenchymal stem cells enhance growth and metastasis of colon cancer.

Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed α-smooth muscle actin and platelet-derived growth factor receptor-ß as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.

Antibodies to Helicobacter pylori and CagA protein are associated with the response to antibacterial therapy in patients with H. pylori-positive API2-MALT1-negative gastric MALT lymphoma.

The aim of this study was to clarify predictive factors for response to eradication therapy in cases of Helicobacter pylori (H. pylori)-positive API2-MALT1-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Sixty-six patients who were examined for H. pylori infection and the presence of the API2-MALT1 chimeric transcript and who underwent H. pylori eradication therapy as first-line therapy, were enrolled in this study. Immunohistochemical markers (p53, Ki-67, and BCL10), microsatellite instability, loss of heterozygosity, serum levels of antibodies (anti-H. pylori and anti-CagA), and markers for gastritis (gastrin and pepsinogens) were examined, and the results were compared between patients whose tumors regressed completely after eradication therapy (responders) and patients whose tumors did not regress (non-responders). Of the 66 patients with localized gastric MALT lymphoma, 47 (71.2%) showed complete remission after eradication therapy. None of the H. pylori-negative (n = 9) and/or API2-MALT1-positive (n = 7) patients responded to antibacterial treatment. Of 44 patients with H. pylori-positive API2-MALT1-negative gastric MALT lymphoma, 38 (86.4%) showed complete remission after eradication therapy. Titers of antibodies against H. pylori and CagA protein were significantly higher in the responders than in the non-responders (P = 0.0235 and 0.0089, respectively). No significant difference between the groups was observed for the other factors. In conclusion, measurement of titers of serum antibodies to H. pylori and CagA protein may be useful for predicting the response to eradication therapy in patients with H. pylori-positive API2-MALT1-negative gastric MALT lymphoma.

Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms.

PURPOSE: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells. EXPERIMENTAL DESIGN: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA microarrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice. RESULTS: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors. CONCLUSIONS: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.

[A case report of anaphylactoid purpura with acute abdominal pain secondary to trauma caused by traffic accident].

A 17-year-old man was admitted to our hospital with multiple fractures resulting from traffic accident. After treatment of fractures, his general status was improved. However, one month after traffic accident, he suffered severe pain in the epigastrium. Ultrasonography and computed tomography showed thickening of the intestinal wall in the duodenum, ileum, and ascending colon. Nineteen days after the onset of abdominal pain, small hemorrhagic spots appeared on both of the lower legs. Subsequently, he developed proteinuria and hematuria. Purpura nephritis was diagnosed in biopsy specimens of the kidney. Anaphylactoid purpura associated with traffic accident is very rare and it is difficult to diagnose without skin and renal symptoms.

Rapid progression of Epstein-Barr-virus-positive gastric diffuse large B-cell lymphoma during chemoradiotherapy: a case report.

A 61-year-old woman was referred to our hospital with epigastralgia and appetite loss. Barium examination and upper gastrointestinal endoscopy revealed uneven erythematous mucosa with multiple elevated lesions from the gastric fornix to the upper corpus. Abdominal computed tomography showed thickening of the wall of the fornix and swelling of perigastric lymph nodes, but whole-body gallium scintigraphy and bone marrow examination did not indicate further involvement. Biopsy specimens showed diffuse infiltration of large atypical lymphoid cells in which Epstein-Barr virus (EBV) was detected by in situ hybridization. Diffuse large B-cell lymphoma (DLBCL), stage II1, was diagnosed. Combination chemotherapy [cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)], was given, and this was followed by radiotherapy. Partial remission was achieved by chemotherapy, but the disease progressed rapidly during radiotherapy. Because the reported prognosis of EBV-positive DLBCL is unfavorable, the therapeutic strategy for EBV-positive gastric DLBCL should be considered carefully.

[A case of endocrine cell carcinoma of the ileum: sonographic findings and clinical outcome].

A 56-year-old man, who had been complaining of diarrhea for several months, was admitted for further examination of a hepatic tumor. A needle biopsy of the hepatic tumor suggested metastatic carcinoid tumor. The primary tumor was found in the ileum by extracorporeal sonographic examination and a barium meal study. We performed a partial excision of the ileum, lymph node resection, wedge biopsy of the liver, and catheterization from the right iliac artery to the hepatic artery for intraarterial chemotherapy. The pathological diagnosis was endocrine cell carcinoma of the ileum and local lymph nodes and hepatic metastasis. After surgery, the patient has been treated with continuous intraarterial infusion of CDDP and 5FU. The liver tumors almost disappeared. As of 20 months after the surgery, the patient is well and is being followed in the outpatient clinic.