細谷 好則

A 57-year-old Japanese man had type II c gastric cancer with marked lymph node metastases associated with leukocytosis and elevated granulocyte colony-stimulating factor (G-CSF). Total gastrectomy and distal pancreatectomy with lymph node dissection were performed. Although the primary lesion was negative for G-CSF by histopathological immunostaining, a highly increased G-CSF m-RNA level, measured using reverse transcriptase-polymerase chain reaction in frozen sections, led to a diagnosis of G-CSF-producing gastric cancer. The leukocytes and G-CSF decreased immediately after surgery. He then had an intraabdominal recurrence, and was diagnosed with multiple tumors in his lung and brain, with abnormally elevated leukocytes and greatly increased G-CSF; he died 4 months after the surgery. Autopsy showed intraabdominal recurrence of cancer, with no metastases to the lung or brain, but with multiple brain and lung abscesses. We speculate that the excessively increased neutrophils induced by G-CSF infiltrated the lung and brain and formed abscesses, mimicking metastases.

Schwannomas, known as neurinomas and neurilemmomas, are benign, slow-growing neoplasms originating in any nerve that has a Schwann cell sheath. They rarely occur in the digestive tract, but when they do, the most common site is the stomach,(1,2) and they represent 0.2% of all gastric tumors.(1) Among 150 gastric submucosal tumors (G-SMTs), only 6 gastric schwannomas (4%) have been found.(3) Because gastric schwannomas are usually covered by intact mucosa and principally involve the submucosa and muscularis propria,(1-3) they are categorized as G-SMTs. Although conventional procedures, such as a barium meal and an endoscopic study, are important in the initial evaluation of a GSMT, they cannot provide enough information in the differential diagnosis of a G-SMT. Cross-sectional imaging findings, such as magnetic resonance imaging(4) and transabdominal sonography, may be useful in the detection and characterization of a G-SMT and its relationship with surrounding organs. We describe here the sonographic findings of gastric schwannoma in a 65-year-old patient. To our knowledge, no previous case reported included sonographic documentation.

Extremely well-differentiated adenocarcinoma (EWDA) is an unusual gastric cancer that is histologically too bland to be diagnosed as malignant neoplasm, particularly using biopsy. EWDA may be a gastric counterpart of 'adenoma malignum' or minimal deviation adenocarcinoma (MDA) in the uterine cervix; however, the clinicopathological features of EWDA remain less apparent than those of MDA. A 60-year-old male was complaining of dysphagia. He had been made aware of a small submucosal tumor in the cardia 2 years before the onset of this symptom. Endoscopic ultrasonographic examination revealed a large cardiac tumor consisting of thickened layers, as observed in Borrmann type IV. Three mucosal biopsies suggested only benign changes including adenoma and hyperplastic polyps. At the fourth biopsy, cytologically bland columnar cells were located in the submucosa along with stromal fibrosis and laminated stones. The possibility that non-neoplastic aberrant pancreas with lithiasis formed the tumor was denied at laparotomy by a frozen section that revealed benign-looking glands invading the diaphragm. Immunohistochemically the cancer glands were positive for CA19-9 and human gastric mucin, but not for p53 or MUC2. To our knowledge, this is a previously unknown combination of EWDA and psammomatous calcification in the stomach.

BACKGROUND: TS-1 (1M tegafur-0.4M 5-chloro-2,4-dihydroxypyrimidine-1M potassium oxonate) has a high single-agent response rate, of more than 40%, for gastric cancer; however, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effects. The alternate-day dosage of pyrimidine fluoride anticancer drugs could reduce their adverse effects without compromising their effects. We attempted an alternate-day therapy with TS-1 aiming at the avoidance of adverse effects and significantly longer duration of administration. METHODS: We observed patients for clinical effects and adverse effects under alternate-day dosage of TS-1, and determined blood 5-fluorouracil (FU) levels. The judgment of clinical effects was based on the New Guidelines to Evaluate the Response to Treatment in Solid Tumors (RECIST), whereas the evaluation of adverse effects was based on the National Cancer Institute NCI-common toxicity criteria (CTC). RESULTS: In 72 (78%) of 92 patients, the TS-1 regimen was converted to the alternate-day dosage because of adverse effects. Twenty patients were treated with the alternate-day dosage regimen from the start because of the fear of adverse effects. The alternate-day dosage was clinically effective, as 28 of 34 patients after relatively curative resection remained alive and free from recurrence. The median survival time of 58 patients after noncurative resection or with unresectable or recurrent cancer was 332 days. Fifty-three percent of these 58 patients achieved partial response and stable disease of more than 12 weeks' duration. We followed time-dependent changes in blood 5-FU levels in 36 of the patients on alternate-day therapy, in whom TS-1 had been administered daily before being administered every other day. The trough level was significantly lower when TS-1 was administered on alternate days, and blood 5-FU reached a peak at sufficiently effective levels at 2 h even after administration on the alternate-day basis. CONCLUSION: . This study demonstrated that, compared with daily administration, alternate-day administration of TS-1 reduces adverse effects, and simultaneously ensures effective blood levels and provides sufficient clinical effects.TS-1 (1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 M potassium oxonate) has a high single-agent response rate, of more than 40%, for gastric cancer; however, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effects. The alternate-day dosage of pyrimidine fluoride anticancer drugs could reduce their adverse effects without compromising their effects. We attempted an alternate-day therapy with TS-1 aiming at the avoidance of adverse effects and significantly longer duration of administration.

We report a case of tracheoesophageal fistula (TEF) secondary to chemotherapy for primary thyroid lymphoma. A 65-year-old man with a short history of a rapidly enlarging neck mass was diagnosed as having thyroid lymphoma of diffuse, large B-cell type. The TEF occurred during the first course of chemotherapy including cyclophosphamide, doxorubicin, vincristine and prednisolone. After placing a feeding gastrostomy without oral intake, eight cycles of chemotherapy were completed and complete remission was achieved. Although the cervical mass disappeared, TEF and esophageal stenosis persisted. Total thyroidectomy and resection of the stenotic cervical esophagus were carried out followed by interposition of the revascularized jejunum and its mesenteric patch to cover the TEF. This seems to be the first report of a TEF caused by chemotherapy for primary thyroid B-cell lymphoma. A variety of treatments for TEF including simple closure, tracheal resection, colonic bypass and muscle flap have been reported with low success rates. Our procedure using a jejunal mesenteric patch seems to be unique and may be a new treatment strategy for TEF.

Background/Aims: To investigate the technical ease and results of gasless laparoscopy-assisted distal gastrectomy with lymph node dissection via mini-laparotomy using abdominal wall lift for early gastric cancer. Methodology: We submitted 20 patients to laparoscopy-assisted distal gastrectomy for early gastric cancer located in the middle or lower stomach. The initial 10 cases underwent perigastric lymph node dissection (D1), and the subsequent 10 cases received further dissection around the left gastric and common hepatic arteries (D1+a). Mini-laparotomy was placed at the beginning of the procedure. We lifted up the laparotomy and the subcutaneous tissue around the umbilicus by retractors. We accomplished the dissection, resection and reconstruction mainly via the mini-laparotomy using a direct view and a laparoscopic image. Results: Two cases were converted to open. The operative time was significantly longer in D1+a (225+/-49 min) than in D1 (172+/-38 min). Blood loss was significantly more in D1+a (247+/-155mL) than in D1 (109+/-60mL). There was no difference between the two groups in terms of days to first flatus, first oral intake or discharge from the hospital. Postoperative complications included 2 wound infections each in D1 and D1+a group, and 1 anastomotic stenosis in D1+a group. Conclusions: Gasless laparoscopy-assisted distal gastrectomy with D1+a via mini-laparotomy using abdominal wall lift seems to be feasible and useful for early gastric cancer.

An 18 cm x 16 cm x 10 cm tumor of the stomach, invading the left lobe of the liver, pancreatic body and tail, and transverse colon, with peritoneal deposits on the major omentum, was resected by total gastrectomy plus left hepatic lobectomy, transverse colectomy, distal pancreatectomy, splenectomy, and omentectomy. Histopathologically, the tumor consisted of large uniform cells with significant nuclear atypia, showing solid growth patterns with occasional small nests without adenocarcinoma components. Immunohistochemical investigations of the neoplastic cells confirmed the tumor as a neuroendocrine (NE) carcinoma. molecular analyses disclosed loss of heterozygosity at the MEN1 gene locus on chromosome 11q13. Recurrence occurred at the hepatic hilus and incurred obstructive jaundice 2 months after surgery. Following percutaneous transhepatic biliary drainage, intensive chemotherapy (20 mg/m(2) cisplatin on days 1-5 div, 100 mg/m(2) etoposide on days 1, 3, and 5 div, and 800 mg/m(2) 5-fluorouracil on days 1-5 bolus iv) was started. The recurrent tumor shrank dramatically, and could not be detected on image modalities after five courses of chemotherapy. The patient was well and free of symptoms without biliary drainage for 5 months. Then he began to present with jaundice again, and died of acute massive dissemination 7 months after surgery. An aggressive form of NE carcinoma has been known to be associated with an extremely poor prognosis. However, it is notable that treatment with extensive surgery and intensive chemotherapy could contribute to an improvement in quality of life even if the beneficial effect lasted for only half a year.

Background: The advisability of endoscopic mucosal resection (EMR) for treatment of large superficial gastric cancers has been challenged. For more reliable en bloc resection, a new method of EMR was developed that uses a viscous substance, sodium hyaluronate, and two newly designed devices. Methods: A large superficial gastric cancer was treated with this new EMR technique. Sodium hyaluronate was injected into the submucosa and mucosal incisions were made with a needle-knife. The newly developed incision forceps and flat-ended transparent hood were used for submucosal incisions. Results: The large cancer was successfully resected endoscopically as a single piece of mucosa 6 cm in diameter without complication. Histopathologic evaluation of the specimen confirmed that the resection was curative. Conclusions: EMR with sodium hyaluronate along with two new devices may be a reliable method for en bloc resection of large superficial gastric lesions.

The liver is the first target organ for malaria parasites immediately after the bite of an infected mosquito. We studied local immunization of malaria DNA vaccines at the site of the liver using a gene gun as a useful tool for in vivo transfection of foreign genes. A malaria DNA vaccine consisting of the Plasmodium berghei circumsporozoite protein (PbCSP) gene plus the mouse IL-12 gene was bombarded directly by a gene gun into mouse liver once or into the skin twice. A marked protective effect was induced by gene bombardment into the liver (more than 71%) compared with that into the skin (less than 33%). A Th1-type immune response and high production of iNOS were observed in the hepatic lymphocytes from mice bombarded into the liver, resulting in more effective protection compared with those bombarded into the skin. These results provide an important implication on the development of efficient malaria vaccine strategies. (C) 2000 Academic Press.

Using a hand-held gene gun, we examined the effects of murine interleukin-12 (IL-12) gene transfection on metastatic tumors. AH 130 cells at high (1 x 107) and low (1 x 106) doses were inoculated into the liver of Donryu rats through the portal vein. On the twelfth day following tumor inoculation, the hepatic surface was bombarded with IL-12 cDNA (4 μg)-coated gold particles emitted by pressurized helium gas (300 psi). The corresponding amount of β-galactosidase (β-gal) cDNA was injected as a control in the same manner. The high-dose model was highly fatal and used for estimation of the survival rate. The low-dose model was investigated to evaluate alterations in the number of tumors, histological findings, and cytokine expression in the liver and spleen. Non-tumor-bearing rats were employed for study of any adverse effects gene gun shots induce on body weight, peripheral blood cell counts, and liver function. The IL-12 gene therapy was effective in terms of the 60-day survival rate (IL-12 50% vs. control 15%, p &lt 0.05). Seven days after DNA transfer the average number of metastatic tumors in the liver increased in the control group, while it diminished in the gene therapy group. Histological examination revealed that most tumor cells in the control group were viable, whereas some of those in the IL-12 group underwent necrotic changes accompanied by massive lymphocytic infiltration. IL-12 and IFN-γ were expressed in the liver and spleen in greater amounts in the IL-12 group than in the control. No remarkable adverse effects were expressed in non-tumor-bearing rats undergoing gene bombardment either with β-gal or IL-12 genes. Thus, this procedure may be applied clinically as a promising therapeutic option for metastatic tumor of the liver. A hand-held gene gun seems especially useful for transfection during laparotomy due to its ability to accurately and instantaneously inject exogenous genes under direct vision. © 2000, The Japanese Society of Strategies for Cancer Research and Therapy. All rights reserved.

We tested the effect of tamoxifen alone and tamoxifen plus 5-fluorouracil (5-FU) on proliferation of two different types of gastric cancer cell Lines using the WST-1 method. A high dose of tamoxifen suppressed the proliferation of KATOIII cells (poorly differentiated adenocarcinoma), but MKN28 cells (well-differentiated adenocarcinoma) were not affected. The combination of the two drugs resulted in a synergistic anti-proliferative activity on KATOIII cells. On the other hand, in the combination therapy, tamoxifen stimulated MKN28 cells to proliferate in a dose-dependent manner. TGF-beta 1 secretion was not changed in KATOIII cells by tamoxifen plus 5-FU treatment but was down-regulated in MKN28 cells. Both cancer cell lines were judged as intracellular estrogen receptor (ER) negative. These data suggest that the anti-proliferative effects of tamoxifen plus 5-FU on KATOIII cells were not dependent on ER expression or TGF-beta 1 secretion. On the other hand, their proliferative effects on MKN28 cells might be, in part, caused by the reduced secretion of TGF-beta 1. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.

We have studied extensively the effects of cytokine gene transfection with a hand held gene gun on solid cancer models in the rat. A review of the results shows that interleukin-12 (IL-12) gene therapy was more effective than tumor necrosis factor-α (TNF-α) therapy against a rat subcutaneous tumor model, and that a synergetic effect was obtained by combined therapy (IL-12 plus TNF-α). IL-12 effectively suppressed the tumor growth and prevented metastasis. The anti-tumor effect of IL-12 gene therapy was then examined using a liver metastatic model. IL-12 gene therapy significantly improved survivals of the rats with liver metastases. A gene gun does not require a viral-vector and is able to introduce foreign genes immediately, in vivo, resulting in high gene expression at a local lesion. Therefore, from the clinical point of view, this technique might be useful as an intraoperative gene therapy for liver metastases. However, some issues still remain, such as the kinds of cytokine genes or the combination to be used, and organ damage caused by high-pressure bursts.

Foregut-derived neuroendocrine (NE) tumors occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty- nine sporadic NE tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine pancreatic tumors) as well as two hindgut-derived rectal carcinoids for somatic MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE tumor (D172Y), the corresponding germline DNA showed the same mutation, suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene mutations and deletions may play a crucial role in the tumorigenesis of a subset of foregut-derived NE tumors. Sporadic MEN1 syndrome may occur as sporadic NE tumor of the pancreas.

We studied the effects of biological response modifiers (BRMs), OK-432 and PC-C203U on induction of tumor ceil apoptosis and expression of cytokine (IL-8, TNF-α, IL-1β, and IFN-γ) mRNA in the abdominal organs. Sixty-seven percent of BALB/c mice bearing BAMC-1 tumor cells survived after the OK-432 treatment, but 67% of the animals died with the use of PC-C203U. Both treatments induced tumor cell apoptosis detected by DNA fragmentation. There was no significant difference of expression of cytokine mRNA in the liver and spleen between the OK-432 and PC-C203U treatment, but there was a tendency to enhanced IL-1β mRNA expression in the milky spot which has been considered to be a site for neutrophil mitosis in the OK-432, compared with in the PC- C203U-treated mice. Further study is needed to reveal mechanism of the difference in efficacy of the anti tumor effect between BRMs.

Using a hand-held gene gun which accelerates DNA-coated microparticles, we examined the effect of interleukin-12 (IL-12) and/or tumor necrosis factor-α (TNF-α) gene transfection a rat solid tumor model. Yoshida sarcoma cells were inoculated subcutaneously into the chests of Donryu rats. Then 4μg of IL-12 and/or TNF-α DNA-coated gold (Au) particles was injected into the tumor by pressurized helium (He) gas at 400psi (1psi=6,890Pa) on day 5 and 7 after tumor inoculation. The corresponding dose of β-galactosidase was given as a control. Compared with the control, injection of TNF-α, IL-12, and IL-12 plus TNF-α effectively inhibited tumor growth and improved the survival rate. TNF-α alone prolonged the survival of tumor-bearing rats, but the animals still died within 41 days after tumor injection. On the other hand, IL-12 alone and IL-12 plus TNF-α completely cured 20% and 40% of the rats, respectively. IL-12 plus TNF-α gene therapy using the gene gun showed a synergetic effect on the survival of tumor-bearing rats. This procedure might useful for the clinical treatment of solid cancer. In particular, there is a possibility of intraoperative gene transfection because the gene gun can introduce multiple genes very rapidly. © 1998, The Japanese Society of Strategies for Cancer Research and Therapy. All rights reserved.