Naoto Kurihara

Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer

We reported previously that a new Western-style diet (NWD) for 18 months, consisting of elevated lipids and decreased calcium, vitamin D and methyl-donor nutrients, induced colonic tumors in normal C57Bl/6 mice [Newmark, H.L. et al. (2001) A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871-1875], suggesting a new mouse model for human sporadic colon cancer. Here, we have extended this study during a longer feeding period of 2 years wherein tumor formation, tumor inhibition by addition of dietary calcium and vitamin D and their effects on gene expression were determined. We also similarly tested individual supplements of methyl donor (transfer) nutrients (folic acid, choline, methionine and dietary fiber), but these had no significant effect on colonic tumor incidence or multiplicity, whereas supplementation with combined calcium and vitamin D produced significant decrease in both colon tumor incidence and multiplicity, during 2 years of feeding. No visible colonic tumors were found at 6 months, very few at 12 months, more at 18 months and significantly at 24 months. In a related study of gene changes of the mouse colonic mucosa at 6 months of feeding taken from this study, long before any tumors were visibly detectable, indicated altered profiles of gene expression linked to later risk of dietary initiation of colon tumor formation. This type of early genetic altered profile, an indication of increased risk of later colonic tumor development, may become a useful tool for prediction of colon tumor risk while the colon grossly still appears histologically and physiologically normal.

Heat-shock protein 60 homologue of Helicobacter pylori is associated with adhesion of H. pylori to human gastric epithelial cells.

A previous study reported a relationship between the expression of heat-shock protein 60 (HSP60) by Helicobacter pylori and its adhesion to human gastric carcinoma (MKN45) cells. To examine whether the HSP60 homologue of H. pylori is associated with the adhesion of H. pylori to human gastric epithelial cells, an inhibition assay of adhesion of H. pylori to MKN45 cells was performed by flow cytometric analysis with monoclonal antibody (MAb) designated as H20 recognising HSP60 of H. pylori. The rate of adhesion of H. pylori pretreated with MAbH20 to MKN45 cells was lower than that of untreated H. pylori. Primary human gastric epithelial cells from a patient with gastric cancer were also prepared for comparison in the inhibition assay with MAbH20. H. pylori adhered to the primary human gastric epithelial cells, and this adhesion was significantly inhibited by MAbH20. These results suggest that the H. pylori HSP60 homologue recognised by MAbH20 might be associated with the adhesion of H. pylori to primary human gastric epithelial cells as well as to cultured gastric cancer cells.

Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high-dose infusions

A pharmacokinetic analysis of cis‐diamminedichloroplatinum (II) (DDP) was conducted comparing low‐dose daily bolus infusions, and high‐dose drip infusions. Eight patients with gastric cancer were treated with low‐dose daily bolus infusions of DDP to a total daily dose of 75 mg/m2 bid for 5 days. Four patients with esophageal cancer and one patient with gastric cancer were treated with high‐dose drip infusions of DDP to a total daily dose of 70–80 mg/m2. Side effects were assessed in all the patients, and the platinum concentration in plasma was determined by an atomic absorption method. The peak plasma concentration (Cmax) and area under the curve (AUC) were calculated in four cases of the low‐dose therapy, and three cases of the high‐dose therapy. The side effects of DDP were evaluated according to the World Health Organization (WHO) grading, paying particular attention to nausea/vomiting, appetite loss, renal toxicity, and bone marrow suppression. The incidence of nausea/vomiting and appetite loss was significantly reduced with low‐dose daily bolus infusions when compared to the high‐dose drip infusions. Bone marrow toxicity and renal toxicity were similar with both administration methods, although hydration was required for the high‐dose drip infusions to prevent renal toxicity. The peak plasma concentration (Cmax) of total and free platinum, and the area under the curve (AUC) of total platinum, were similar with both administration methods, while the AUC of free platinum was higher with the low‐dose daily bolus infusions compared to the high‐dose drip infusions. The time when the concentration of total platinum was >1 μg per ml (holding time) was significantly longer with the high‐dose drip infusions than with the low‐dose daily bolus infusions. The present study suggests that low‐dose daily bolus infusions of DDP would be useful in reducing gastrointestinal toxicity, without reducing the area under the curve which is important for antitumor activity.

Induction of secretion of interleukin-8 from human gastric epithelial cells by heat-shock protein 60 homologue of Helicobacter pylori

Escherichia coli cells expressing fusion proteins consisting of beta-galactosidase and bacterial heat-shock protein (HSP) 60 of E. coli, Yersinia enterocolitica or Helicobacter pylori were constructed, and designated as HY1, HY2 or HY3, respectively. Fusion proteins prepared from HY2 and HY3 induced secretion of interleukin-8 (IL-8) from human gastric epithelial KATOIII cell cultures. On the other hand, the parent strain (E. coli pop2136), PEX (pop2136 transformed by vector) and fusion protein prepared from HY1 did not induce IL-8 secretion from KATOIII cells. Other human gastric (MKN45) and non-gastric cell lines (Int 407 and A549) did not secrete IL-8 following treatment with these proteins. These results indicate that H. pylori HSP60 induces IL-8 secretion from human gastric cells and the levels of IL-8 differ among the various gastric cell lines, suggesting that HSP60 might be an important virulence factor associated with chronic gastric inflammation following H. pylori infection in man.

Surgically treated Cronkhite-Canada syndrome associated with gastric cancer

Cronkhite-Canada syndrome is generally accepted to be a benign disorder, with 374 reported cases to the present. Worldwide, there have been 18 previously reported cases of Cronkhite-Canada syndrome associated with gastric cancer. In this report we describe a case of a 52-year-old man with the clinical features of Cronkhite-Canada syndrome combined with gastric cancer. Although the gastric tumor was located at the antrum of the stomach, we performed a total gastrectomy because of the edematous swelling and high risk of malignancy in the remnant stomach. As Cronkhite-Canada syndrome may be a premalignant condition for gastric cancer, as well as for colorectal cancer, we suggest periodic examination of the stomach, colon, and rectum for patients with Cronkhite-Canada syndrome.

Partial resection of the second portion of the duodenum for gastrointestinal stromal tumor after effective transarterial embolization.

We report herein the case of 64-year-old man with gastrointestinal stromal tumor (GIST), who was treated by partial resection of the duodenum after preoperative transarterial embolization. He presented to our hospital with a history of tarry stools, dizziness, and severe anemia (hemoglobin, 7.5 g/dl). Gastroduodenal endoscopy revealed the presence of a submucosal tumor in the second portion of the duodenum. The presence of the tumor was subsequently confirmed by double-contrast gastrointestinal radiography and abdominal computed tomography. Super-selective angiography showed tumor staining fed from the anterior and posterior superior pancreaticoduodenal arteries, and the inferior pancreaticoduodenal artery. Two weeks after transarterial embolization through these vessels, the tumor size was found to have shrunk to 40% of its original size. Partial resection of the duodenum was performed and absence of tumor cells at the surgical margin was confirmed by intraoperative frozen-section examination. Histopathological examination revealed that the duodenal submucosal tumor consisted of spindle cells, and immunohistochemical analysis revealed positive tumor staining for c-kit protein, CD34 and α-smooth muscle actin (SMA), and negative staining for desmin and S-100; the positivity rate for MIB-1 staining was 2.2%. Based on these findings, the tumor was diagnosed as a GIST of low-grade malignancy, classified as the muscular type. It is considered that preoperative treatment of duodenal GISTs, such as transarterial embolization, may be useful for reducing the extent of resection, from pancreaticoduodenenctomy to a partial resection.

Antitumor activity of cis‐diamminedichloroplatinum II against human tumor xenografts depends on its area under the curve in nude mice

A pharmacodynamic analysis of cis‐diamminedichloroplatinum(II) (DDP) was conducted using two human gastric cancer xenografts, SC‐1‐NU and MKN‐45, and one human breast cancer xenograft, MX‐1, grown serially in BALB/c nu/nu mice. DDP was administered intraperitoneally (ip) at a total dose of 5, 10, or 20 mg/kg in a schedule of q7d × 3 or (qd × 5) × 3. DDP was also administered ip to BALB/c +/? mice, whose plasma was used for the assay of total and free platinum by the atomic absorption method. A total dose of 20 mg/kg DDP seemed to be the maximum tolerated dose that was effective on MX‐1 and SC‐1‐NU. When the totally administered doses were equivalent, the antitumor effects of the q7d × 3 and (qd × 5) × 3 schedules were similar to each other. The antitumor activity of DDP against MKN‐45 was dependent on the total administered dose as well as the area under the curve of free and total platinum in the plasma. Side effects were significantly reduced using a schedule of (qd × 5) × 3 in terms of body and spleen weight loss when a total of 10 or 20 mg of DDP per kg was administered. These results suggest that DDP would be useful when administered using a daily schedule for obtaining the same antitumor activity as that of bolus injection but with reduced adverse effects.

Hepatoid adenocarcinoma of the stomach with multi-nucleated giant cell proliferation in a 100-year-old man

Few cases of gastric carcinoma with infiltrating multi‐nucleated giant cells (MGCs) have been reported, and giant cells infiltrating the gastric carcinoma were previously described as osteoclast‐like giant cells (OGCs). However, hepatoid adenocarcinomas have never been reported previously, and the present case is extremely rare. A 100‐year‐old Japanese man with gastralgia was found to have a mass in his gastric body. Histological examination showed a poorly differentiated adenocarcinoma with infiltration of MGCs. Vascular and lymphatic invasion were noted but there were no metastases. Almost all the tumor comprised cells with hepatoid‐like features. The MGCs proliferated, with infiltration of lymphoid cells. A few MGCs contained mucous material in their cytoplasm, indicating these were foreign‐body giant cells. Immunohistochemically, the hepatoid‐like components were positive for AFP, and staining with polyclonal antibodies against carcinoembryonic antigen (CEA) showed the canalicular pattern. We concluded that this component was hepatoid adenocarcinoma. The MGCs were positive for CD68, and surrounding infiltrating lymphoid cells were diffusely positive for CD3. Infiltration of MGCs in gastric cancer may represent a cellular immune response against gastric cancer invasion. Further studies are required to elucidate the etiology of MGCs in gastric cancer.

Gastric plasmacytoma: report of a case.

A 54-year-old man with primary gastric plasmacytoma is herein reported. After the patient had been diagnosed as having malignant lymphoma by gastrofiberscopy and a radiologic upper GI examination, a total gastrectomy was performed. Both histological and immunohistochemical studies showed plasmacytoma cells infiltrating the entire stomach wall, producing IgM-λ, and indicating a final diagnosis of primary gastric plasmacytoma. Monoclonal immunoglobulin was not detected in the serum throughout the course. The case is discussed with reference to other reported cases of primary gastric plasmacytoma.

Serial growth of human malignant fibrous histiocytoma xenografts in immunodeficient mice

Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas of adulthood, the only treatment for which involves surgical resection of the extremities and retroperitoneum, while no standard postoperative adjuvant chemotherapy has been established. We report herein on the establishment of a serially transplantable MFH strain in immunodeficient mice. An intraperitoneal tumor was resected from a patient with multiple recurrent MFH, inoculated into the subcutaneous tissue of mice with severe combined immunodeficiency (SCID), and established as a serially transplantable MFH strain, MH-1. The chemosensitivity of MH-1 was similar to that of the original fresh surgical specimen, as confirmed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) test. We believe that this serially transplantable strain will be useful for further studies on chemotherapy effective against MFH.