Biomedical subjects

Yoshiyuki Yamaguchi

Publications and source records attributed to Yoshiyuki Yamaguchi.

At least 19 recordsLinked to original sources

PubMed2006

Maturation of dendritic cells and T-cell responses in sentinel lymph nodes from patients with breast carcinoma.

BACKGROUND: Methods for identifying sentinel lymph nodes (SNs) and their clinical significance have been established. Recent advances in molecular immunology have enabled the analysis of precise immune responses. The objective of the current study was to clarify the dendritic cell (DC) maturation, T-helper type 1 (Th-1) and Th-2 responses, and regulatory T-cell responses of SNs in patients with breast carcinoma. METHODS: SNs and non-SNs were identified by radioguided and blue dye-guided methods in 70 consecutive patients with clinically lymph node negative (N0) breast carcinoma. Lymphocytes were collected from SNs and non-SNs and were subjected to flow cytometric analysis (FCM) using antibodies of CD83-fluorescein isothiocyanate (FITC), CD80-phycoerythrin (PE), CD86-PE, CD40-PE, human leukemic D-related antigen (HLA-DR)-FITC, CD4-FITC, and CD25-PE. Total RNA was extracted from SNs and non-SNs, and the expression of CD83, interleukin 12p40 (IL-12p40), interferon gamma (IFN-gamma), IL-4, IL-10, and Foxp3 was evaluated by using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The immunologic status of SNs was analyzed further with regard to micrometastases, which were identified as negative microscopically but positive according to an RT-PCR analysis that was specific for mammaglobin. RESULTS: SNs were detectable in 70 of 71 consecutive patients (98.6%) with clinically N0 breast carcinoma. Fourteen of 70 patients (20.0%) had positive metastasis in SNs. When SNs were compared with non-SNs in 56 metastasis-negative patients, FCM revealed that HLA-DR-positive, CD80-positive, CD86-positive, and CD40-positive cell populations were decreased significantly in SNs. RT-PCR analysis demonstrated that, among 44 patients with metastasis-negative SNs, the expression levels of CD83 and IFN-gamma mRNA were significantly lower in SNs compared with non-SNs. Immunologic parameters also were compared between 44 metastasis-negative SNs and 14 metastasis-positive SNs. The metastasis-positive SNs demonstrated significantly higher expression of CD83, IL-12p40, IFN-gamma, IL-10, and Foxp3 mRNA than the metastasis-negative SNs. Correction of micrometastasis detected by mammaglobin enhanced these differences consistently. CONCLUSIONS: In patients with breast carcinoma, cellular immune responses, from DC maturation to Th-1 responses, appeared to be less active in SNs compared with non-SNs before metastasis developed. Once metastasis was established in SNs, DC maturation was triggered and was followed by the up-regulation of Th-1 responses, which may reflect antigen-specific immune responses in SNs. Unlike DC maturation and Th-1 responses after metastasis in SNs, up-regulation of Th-2 and regulatory T-cell responses developed in parallel.

Adult↗

PubMed2006

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: possible application for compensatory anti-inflammatory response syndrome.

Immunological parameters were measured in order to elucidate a postoperative immunosuppression mechanism in transthoracic esophagectomy for patients with esophageal cancer. Moreover, lymphokine-activated killer (LAK) cells were transferred just after the surgery to overcome the postoperative immunosuppression. Fifteen consecutive patients who underwent transthoracic esophagectomy were subjected to the postoperative measurement of immunological parameters. Ten patients who underwent open cholecystectomy served as controls. Heparinized venous blood was obtained pre- and postoperatively, and serum levels of cytokines IL-6 and IL-10 and immunosuppressive acidic protein (IAP) were measured. Peripheral blood lymphocytes were harvested and analyzed by flow cytometry for phenotype detection and by a mixed lymphocyte reaction for detecting concanavalin (Con)-A-induced or -non-induced suppressor activity. Another 29 consecutive patients who underwent transthoracic esophagectomy were randomly enrolled in a postoperative immunotherapy trial either with or without lymphokine-activated killer cells. It was found that, in the esophagectomy group, IL-6 and IL-10 increased postoperatively and peaked on day 1, followed by an increase in IAP, peaked again on day 4, with a profound decrease in helper and cytotoxic T-cell subsets, followed by increases in Con-A-induced (on day 7 or later) and spontaneous (on day 10) suppressor activities. These changes were minimal in the cholecystectomy group. LAK cell transfer restored the postoperative decrease in the helper and cytotoxic T-cell population, and there was a trend of reduction for postoperative remote infection such as pneumonia and surgical site infection in the LAK therapy group. Taken together, we would like to propose the existence of a postoperative immunosuppression cascade consisting of increases in cytokines and immunosuppressive proteins, decreases in helper and cytotoxic T-cell populations, and the development of suppressor T-cell activities in surgery for esophageal cancer. Postoperative adoptive transfer of LAK cells may be a novel clinical application in surgery for esophageal cancer as a means of treating this postoperative immunosuppressive condition that may be identical to the status of compensatory anti-inflammatory response syndrome (CARS).

Aged↗

PubMed2006

Generation of tumor-reactive effector lymphocytes using tumor RNA-introduced dendritic cells in gastric cancer patients.

Anti-tumor effector cells were generated by stimulating peripheral blood lymphocytes with cultured dendritic cells (DCs) and mRNA extracted from the gastric cancer cell line MKN45 or ascites tumor cells of gastric cancer patients. DCs were generated from an adherent fraction of peripheral blood mononuclear cells (PBMCs) in the presence of GM-CSF and IL-4. mRNA was extracted from tumor cells and subjected to T7-amplification. The DCs were electroporated (150 V/150 microF) with amplified mRNA and used after maturation with TNF-alpha to stimulate PBMCs to generate tumor RNA-introduced DC-activated killer (TRiDAK) cells. It was found that tumor RNA could efficiently be introduced into cultured DCs by electroporation (55% efficiency, 78% viability), and tumor RNA-introduced DCs could reproducibly stimulate lymphocytes to be tumor-reactive TRiDAK cells. The TRiDAK cells expressed an IFN-gamma response specific for tumor cells, but not for normal cells. Mock DCs or normal cell RNA-introduced DCs did not induce any killer cells. RNA-specific recognition of the effector cells generated was demonstrated using an amplified EGFP-mRNA system. The tumor killing activity of TRiDAK cells was inhibited not only with the anti-HLA class I antibody but also with the anti-HLA class II antibody as well as the anti-TCR antibody. TRiDAK cells reactive with autologous tumor cells could be generated in a CEA-positive gastric cancer patient with malignant ascites, in whom effector cell generation using DCs and CEA peptides had failed. These results suggest that TRiDAK cell generation is safe, feasible, and active in gastric cancer patients with malignant ascites, and is superior to other effector cell generation systems using DCs and epitope peptides. The adoptive immunotherapy of cancer using TRiDAK cells may be warranted in a clinical setting. This is the first study investigating anti-tumor effector cell generation using cultured DCs and tumor mRNA from gastric cancer cells.

Antigen-Presenting Cells↗

PubMed2006

Adoptive immunotherapy using autologous lymphocytes sensitized with HLA class I-matched allogeneic tumor cells.

A 29-year-old female breast cancer patient with multiple bone metastases (HLA-A2) was treated with adoptive transfer using autologous peripheral blood mononuclear cells (PBMCs) activated with the HLA-A2-matched allogeneic GC022588 gastric cancer cell line and interleukin-2 plus an immobilized anti-CD3 antibody culture system. The relief of bone pain in parallel with a decrease of serum carcinoembryonic antigen levels was obtained just after the administration of GC022588-activated effector lymphocytes, and a good quality of life was accomplished for 4 months. The GC022588-activated effector lymphocytes included 44% CD4+, 77% CD8+, and 26% CD4+CD8+ phenotypes, and expressed 25% killing activity against GC022588 stimulator cells at an E/T ratio of 50:1. T cell receptor (TCR) usage analysis for the effector cells showed oligoclonal expression of TCRVbeta1, 3, 9, and 11, especially TCRVbeta5.2, 12, 13.1 and 17, and their killing activity was significantly inhibited in the presence of anti-TCRalphabeta antibody and anti-TCRVbeta12 antibody. SSCP analysis revealed clonotypic bands of TCRVbeta12. These results suggest that shared antigens exist between breast and gastric adenocarcinomas. Allogeneic tumor cells can stimulate PBMCs to generate effector cells with selected TCRCDR3 usages that recognize tumor antigens. These effector lymphocytes may be good candidates for the adoptive immunotherapy of cancer.

CD3 Complex↗

PubMed2005

Generation of antigen-presenting cells using cultured dendritic cells and amplified autologous tumor mRNA.

Novel antigen-presenting cells (APCs) were generated using cultured dendritic cells (DCs) and amplified tumor mRNA, and the potential of tumor antigen-reactive T cell induction by the tumor RNA-introduced DCs (DC/tumor RNA) was analyzed in a patient with melanoma antigen-encoding gene (MAGE3)-positive malignant melanoma of the esophagus. DCs were generated from an adherent fraction of peripheral blood mononuclear cells in the presence of granulocyte macrophage colony-stimulating factor and interleukin-4. Tumor mRNA was purified from tumor tissue, amplified in vitro using a T7 RNA polymerase system, and then introduced into DCs by electroporation (150 V/150 microF or 100 V/200 microF). The gene introduction efficiency was 44-55% as measured by enhanced green fluorescent protein reporter gene expression, and the viability of RNA-introduced DCs was approximately 80%. DC/tumor RNA could induce tumor antigen-reactive cytotoxic T lymphocytes (CTLs) in an mRNA-specific manner, but had no effect on the self-antigen-reactive T cells. DC/tumor RNA could induce the polyspecific antigen-reactive CTL responses mediated by both human leukocyte antigen class I and class II molecules, whereas MAGE3 peptide-pulsed DCs induced only the monospecific MAGE3-reactive CTL responses mediated by human leukocyte antigen class I molecules, showing the superiority of the DC/tumor RNA over the DC/peptide. It is suggested that the use of DC/tumor RNA as antigen-presenting cells may be more effective, convenient and practical for the DC-based anti-cancer immunotherapy.

Antigen-Presenting Cells↗

PubMed2005

A clinical study of 11 cases of combined hepatocellular-cholangiocarcinoma Assessment of enhancement patterns on dynamics computed tomography before resection.

BACKGROUND AND AIM: : The aim of this study was to identify computed tomography features that contribute to clinical diagnosis of hepatocellular-cholangiocarcinoma. METHODS: : We retrospectively reviewed the clinicopathologic features of 11 patients who underwent hepatectomy for hepatocellular-cholangiocarcinoma between January 1994 and December 2003 at Hiroshima City Hospital and investigated correlation of histopathologic features of surgical specimens with preoperative enhanced computed tomography findings. RESULTS: : Three computed tomography enhancement patterns were observed: an area of hyperenhancement in the early phase and hypoenhancement due to washout of contrast medium in the late phase, resembling hepatocellular carcinoma (Type I, n=4); peripheral enhancement in the early and late phases (Type II, n=2); an area of hyperenhancement in the early phase and an area of slight delayed enhancement in the late phase (Type III, n=4). Histopathologically, all tumors were of mixed morphology (Allen's Type C) comprising hepatocellular carcinoma and cholangiocarcinoma components with transitional features. Computed tomography findings conformed well to pathologic findings. The hepatocellular carcinoma component was predominant in Type I masses. Type II masses showed central necrosis. In Type III masses, the hepatocellular carcinoma-predominant component corresponded to the area of early-phase enhancement and the cholangiocarcinoma-predominant component to the area of late-phase enhancement. CONCLUSIONS: : In Type III tumors, hepatocellular and cholangiocellular components can be identified on the basis of dynamic computed tomography enhancement pattern.

Journal Article↗

PubMed2005

Anterior resection of rectal cancer through a one hand-size incision with or without laparoscopy: proposal of one hand-size incision surgery (OHaSIS).

BACKGROUND: One hand-size incision surgery (OHaSIS) is a surgery that is carried out through one hand-size incision with or without laparoscopy. Safety, feasibility and recovery advantage of the anterior resection of rectal cancer by the OHaSIS were studied. STUDY DESIGN: Nineteen consecutive patients with rectal cancer, consisting of seven rectosigmoid, six upper rectal, and six lower rectal cancers, were treated with anterior resection, including seven high, six low, three super-low, and three partial intersphincteric resections, through a suprapubic longitudinal one hand-size incision. The initial 11 patients were treated in combination with laparoscopy and the following eight patients were treated without laparoscopy. RESULTS: All anterior resections with mesorectal excision were completed in a safe manner with acceptable operative time (average 245 min), blood loss (average 280 g), and postoperative complications without any elongation of the initial incision. When compared with 12 previous high and low anterior resections by conventional open surgery (OS), the 13 high and low anterior resections by the OHaSIS showed equivalent operative time, blood loss, anastomotic procedures of single stapling, lymph node numbers dissected, surgical margin of the anal side of the tumor, and complications. Moreover, analysis of perioperative parameters for surgical invasiveness, including a body temperature >37 degrees C, days of bed rest, and days of use of parenteral narcotics, revealed a recovery advantage in the OHaSIS group compared with that in the OS group. CONCLUSIONS: These results suggest that anterior resection for patients with rectal cancer by the OHaSIS is safe, feasible, and less invasive than conventional OS, and has sufficient operative performance. Although the survival benefit and recurrence rate by this approach must be ensured in a future trial, we would like to propose the new concept of OHaSIS for treating rectal cancer.

Adult↗

PubMed2005

Efficacy of combined sevelamer and calcium carbonate therapy for hyperphosphatemia in Japanese hemodialysis patients.

In Japan, calcimimetics and other phosphate binders such as lantanum carbonate are not available for patients on long-term hemodialysis (HD), so we prospectively evaluated the clinical efficacy of the combination of sevelamer hydrochloride and calcium carbonate (CaCO3) for hyperphosphatemia. The study group comprised 65 HD patients who had been administered CaCO3 (>or=1500 mg/day) for hyperphosphatemia [>or=6.0 mg/dL (>or=1.94 mmol/L)]. At the beginning of the study the dose of CaCO3 was reduced by 1500 mg/day and the patients divided into two groups according to the dose of additional sevelamer hydrochloride: group A 2250 mg/day; group B 3000 mg/day. Oral active vitamin D therapy was unchanged. Fourteen patients (21.5%) dropped out because of adverse effects and of the 51 remaining patients 35 (53.8%) suffered from gastrointestinal problems. Serum phosphate concentration decreased significantly [from 7.5+/-0.8 mg/dL (2.42+/-0.26 mmol/L) to 6.6+/-1.3 mg/dL (2.13+/-0.42 mmol/L), P<0.01] in group B only after the 8 weeks of combination therapy. The calcium-phosphate product (CaxPi) also decreased in group B only [from 74.4+/-13.4 mg2/dL2 (5.99+/-1.07 mmol2/l2) to 63.7+/-15.8 mg2/dL2 (5.13+/-1.27 mmol2/l2), P<0.001]. The combination of sevelamer hydrochloride and CaCO3 is a suitable regimen for hyperphosphatemia treatment in HD patients because it avoids both the hypercalcemia of CaCO3 and the adverse effects of sevelamer hydrochloride when each is used as single-drug therapy. The ability of sevelamer hydrochloride to decrease the serum phosphate concentration is 2/3 (2250/1500 mg) that of CaCO3.

Calcium Carbonate↗

PubMed2005

A single nucleotide polymorphism in the 5' untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer.

OBJECTIVE: Epidermal growth factor (EGF) has many biological functions and plays an important role in the progression of various tumors including gastric cancer. An A-G single nucleotide polymorphism (SNP) at position 61 in the 5'-untranslated region (UTR) of the EGF gene has recently been reported to be associated with different levels of EGF production. We examined whether this polymorphism is correlated with the development and malignant phenotypes of gastric cancer. METHODS: The study population included 200 gastric cancer patients and 230 healthy control subjects. The SNP in the 5'-UTR of the EGF gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The A allele was significantly less frequent in patients than in controls (p = 0.01). Individuals with the A/A or A/G genotype showed a significantly lower risk of gastric cancer than those with the G/G genotype [adjusted odds ratio (OR) = 0.56], whereas the same genotypes were associated with malignant progression of this cancer, e.g. deeper tumor invasion, increased lymph node metastasis and advanced clinical stage, and histological classification in gastric cancer patients (adjusted OR = 1.80, 1.98, 2.26 and 1.89, respectively). CONCLUSIONS: Our findings suggest that the A-G polymorphism of EGF is involved not only in the occurrence but also in the malignant progression of gastric cancer.

5' Flanking Region↗

PubMed2005

[A case report of bowel obstruction due to peritonitis carcinomatosa using combined administration with CPT-11 and CDDP].

We report here a case of recurrent gastric cancer that responded to third-line chemotherapy with CPT-11 and CDDP. The patient was a 61-year-old man with recurrent gastric cancer, who had administered TS-1 for first-line chemotherapy and paclitaxel for second-line chemotherapy. After such therapy, bowel obstruction was revealed due to peritoneal dissemination. The patient underwent third-line chemotherapy with CPT-11 and CDDP after drainage of gastrointestinal juice by nasogastric tube. The treatment schedule for CPT-11 and CDDP therapy consisted of CPT-11 60 mg/m2 div at day 1, day 15 and CDDP 60 mg/m2 div at day 1. It was repeated every 4 weeks. After first administration, the bowel obstruction was improved, so the treatment was continued for 8 months on an outpatient basis. These findings imply that this treatment can be a useful second-line or third-line chemotherapy for unresectable advanced or recurrent gastric cancer.

Ambulatory Care↗

PubMed2005

[Surgical stress].

Explore the source record for details and available documents.

Arachidonic Acids↗

PubMed2005

Neoadjuvant therapy of rectal cancer using oral tegaful-uracil (UFT) plus concomitant radiotherapy--a case report.

A 59-year-old male patient with rectal cancer 2 cm in diameter (T2) at the peritoneal reflection with suspicious left lateral node metastasis was treated with 400 mg of preoperative oral uracil and tegaful (UFT) for 5 weeks, 5 days a week in combination with concomitant radiotherapy of 45 Gy per 25 fractions for 5 weeks. After resting for another 5 weeks, colon fiberscopy, barium enema, and computed tomography revealed a trace of the primary tumor and a 40% shrinkage of the lateral metastasis. The serum CEA level decreased to the normal range during treatment. The adverse effects were nausea, bloody stool and elevation of transaminase, all at grade 1. Low anterior resection with a left hemi-lateral lymphadenectomy was performed through a suprapubic, one hand-size incision without laparoscopy. The preoperative treatment did not affect any operative procedures, and no postoperative complications occurred. The surgical specimen showed that the rectal tumor had been remarkably shrunk by the preoperative treatment, to the level of a superficial type tumor. Histological analysis indicated moderately differentiated adenocarcinoma cells that were present at only 2 mm in diameter in the mucosal layer, 6 mm in the submucosal layer, and 1 mm or less in the muscular layer with scar formation. No metastasis was detected in the 16 lymph nodes dissected, but an organizing tumor thrombus, which had preoperatively been diagnosed as lateral node metastasis, was detected. These results suggest that preoperative oral UFT plus concomitant radiotherapy may be a feasible, tolerable and effective treatment for patients with rectal cancer.

Adenocarcinoma↗

PubMed2005

CD4+CD25+ regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer.

It is well known that immunosuppression may contribute to the progression and chemotherapy-resistance of cancer. Recent studies have demonstrated that lymphocytes with the phenotype of CD4+CD25+ regulatory T cells (T-regs) contribute to immune dysfunction in cancer patients, and a relative increase in CD4+CD25+ regulatory T cells is related to immunosuppression and tumor progression in patients with some malignancies. In the present study, we evaluated the prevalence of T-regs in the peripheral blood of patients with breast cancer and non-small cell lung cancer. The phenotype of lymphocyte CD4+CD25+ cells was analyzed in peripheral blood of patients with breast cancer (n=22) and non-small cell lung cancer (NSCLC) (n=17). The population of CD4+CD25+ cells in CD3+ and CD4+ cells was evaluated by flow cytometric analysis with triple-color staining. Patients with breast cancer did not have a higher percentage of CD4+CD25+ cells in the total CD3+ and CD4+ cells in their peripheral blood than healthy volunteers. In contrast, patients with recurrent NSCLC had significantly higher percentages of CD4+CD25+ cells in CD3+ (47.6%) and CD4+ (71.0%) than healthy volunteers (n=10) who had CD4+CD25+ cells in CD3+ (33.7%, p=0.02) and CD4+ (52.2%, p<0.03). The population of CD4+CD25+ T-regs in the peripheral blood of patients with non-small cell lung cancer was significantly higher than that in healthy volunteers but not in breast cancer patients. These findings suggest that the use of T-reg-targeted immunomodulatory therapy may be a more effective strategy for patients with non-small cell lung cancer than for those with breast cancer.

Adult↗

PubMed2005

Intractable gastrointestinal bleeding from angiodysplasia in a patient of Bernard-Soulier syndrome--report of a case--.

We herein report a case of gastrointestinal bleeding induced by angiodysplasia of the cecum in a case of Bernard-Soulier syndrome with recurrent breast cancer. In spite of endoscopic hemostatic therapy and interventional embolization, she had repeated massive bleeding from the cecal lesion. In addition, she had chronic hepatitis C and progressive liver tumors metastasized from breast cancer, and she finally died of hepatic failure. There are four case reports in the literature describing Bernard-Soulier syndrome with gastrointestinal bleeding angiodysplasia. The reported cases benefited from hormonal, endoscopical hemostasis and surgical therapy. In our case, because of her terminal metastatic breast cancer, only conservative treatments were administered after the third bleed. Both the endoscopic hemostatic method and interventional embolization showed only a temporary effect. Surgical treatment should be considered if the general condition can tolerate a surgical procedure.

Angiodysplasia↗

PubMed2004

A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer.

PURPOSE: Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position -1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the -1562 C/T polymorphism and the development and progression of gastric cancer. METHODS: The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied. RESULTS: Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each). CONCLUSIONS: Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.

Aged↗

PubMed2004

A single nucleotide polymorphism in the MMP-1 promoter is correlated with histological differentiation of gastric cancer.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) plays a key role in cancer invasion and metastasis by degradation of extracellular matrix (ECM) and basement membrane barriers. The 1G/2G single nucleotide polymorphism (SNP) in the MMP-1 promoter at position -1607 bp has been reported to affect the transcriptional activity. In the light of these findings, we investigated whether this SNP in the MMP-1 promoter is associated with the development, differentiation, and progression of gastric cancer. METHODS: The 215 gastric cancer patients and 166 controls were used in this study. The SNP of the MMP-1 promoter was analyzed by PCR-RFLP and sequencing. The genotype frequency was compared between cases and controls, and the association with clinicopathological parameters among cases was studied. RESULTS: The frequency of 1G/2G genotypes in gastric cancer patients was similar to those in controls (p=0.57). The degree of tumor invasion, the presence of lymph node metastasis, and clinical stage showed no significant association with the SNP. On the other hand, we found a significant association with histological differentiation and gender among gastric cancer patients (p<0.05, respectively). CONCLUSIONS: The presence of 2G allele in the MMP-1 promoter did not enhance the risk of gastric cancer; however, it may be involved in differentiation of gastric cancer.

Aged↗

PubMed2004

Establishment of two cell lines from human gastric scirrhous carcinoma that possess the potential to metastasize spontaneously in nude mice.

Few experimental studies have been conducted to clarify the mechanism of development of metastasis in scirrhous carcinoma of the stomach. In the present study, we attempted to establish gastric carcinoma cell lines by incubation of cancer cells collected from the body fluids of patients with gastric cancer. At the same time, xenografting of these cells to nude mice was performed. It was found that, of the gastric carcinoma cell lines thus established, two cell lines, designated as HSC-44PE and HSC-58, formed s.c. tumors with a high infiltrative potential (often invading the lymphatics around the cancer tissue) when implanted. Metastasis to the lymph nodes and lungs was observed in 20-40% of all the animals, indicating that the two cell lines are also capable of metastasizing spontaneously. Through repeated selection, i.e., repeated cycles of removal, culture, and implantation of the HSC cancer cells from metastatic lesions, we obtained 5 subclones of HSC-44PE and HSC-58 (designated as m2509, m2615, m2792, m2917, and m2691), which, when implanted orthotopically, exhibited the following characteristics as compared to the parent cells: (1) a higher percentage take (survival), similar frequency of metastasis, shorter time to metastasis (less than 100 days), and consistent metastasizing potential; (2) a relatively high frequency of metastasis to lymph nodes, including distant metastasis to axillary lymph nodes; (3) the potential to cause occasional bloody ascites; (4) enhanced expression of dysadherin, CD44, and other molecules. This is the first report of cultured scirrhous gastric carcinoma cells showing the potential for spontaneous metastasis.

Adenocarcinoma, Scirrhous↗

PubMed2004

Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment.

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.

Aged↗