Biomedical subjects

Riki Okita

Publications and source records attributed to Riki Okita.

15 recordsLinked to original sources

PubMed2006

Non-palpable ductal carcinoma in situ (DCIS) with microinvasion arising in a radial scar presenting with spiculation alone on mammograms: a case report.

A case of ductal carcinoma in situ (DCIS) with microinvasion arising in a radial scar of the breast is presented. A 57-year-old woman visited our hospital with bloody discharge from her left nipple. There were no abnormal findings on cytology, carcinoembryonic antigen (CEA) level of nipple discharge was <500 ng/ml, and mammograms were normal. After 2 years of careful periodic follow-up, spiculation without a central core appeared on mammograms. The CEA level of the nipple discharge increased to 1,000 ng/ml. Ductgraphy showed a connection between the duct with the discharge and the center of the spiculation. Since these findings suggested malignancy, she underwent segmentectomy of the breast, and pathological examination showed a radial scar and DCIS with microinvasion in the ducts within the radiating bands of fibrous tissues. We discuss the characteristics of a radial scar and its relationship to breast cancer based on our experience and a review of the literature.

Breast Neoplasms↗

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

Successful surgical treatment of aortoesophageal fistula after esophagectomy.

We report a 65-year-old man with complications of aortoesophageal fistula after esophagectomy. A combined middle-lower esophagectomy with remnant gastrectomy was performed for esophageal cancer. The alimentary tract was restored by intrathoracic esophagojejunal anastomosis using a surgical stapler. Twenty-four days later the patient suddenly had hypovolemic shock develop due to aortoesophageal fistula. We performed emergency surgery, and the aortic fistula was directly closed with a 3-0 monofilament using abdominal fascia as a pledget. Thirty-eight days later, alimentary reconstruction was performed using a free jejunal graft. Aortic pseudoaneurysm due to direct closure was predictably detected, and transluminal endovascular stent grafting was indicated.

Aged↗

PubMed2005

Multiple ground-glass opacity in metastasis of malignant melanoma diagnosed by lung biopsy.

Focal ground-glass opacity (GGO) on computed tomography has been reported in several disorders including inflammatory disease and primary neoplastic lesion of the lung. We report a case of malignant melanoma of the nasal cavity metastatic to the lungs in which multiple pulmonary nodules showed GGO. Lung biopsy specimen demonstrated melanoma cells proliferating in a lepidic fashion along the thickened alveolar wall simulating bronchioloalveolar carcinoma. Metastatic lung tumor showing GGO is uncommon.

Adenocarcinoma↗

PubMed2005

Synchronous liver metastases of intracystic papillary carcinoma with invasion of the breast.

A rare case of intracystic papillary carcinoma (IPC) with invasion had synchronous metastases to the liver at presentation. A 57-year-old postmenopausal woman noticed a right breast tumor 7 months prior to admission. Mammography showed an oval mass measuring 3.1 cm in diameter with no calcification, and ultrasonography showed an intracystic tumor with a papillary growth pattern. Fine-needle aspiration cytology revealed adenocarcinoma. Excisional biopsy revealed intracystic solid papillary carcinoma with invasion. The tumor was a clear-cell type with extracellular mucin. Two months after the initial biopsy, a screening ultrasonographic examination of the liver showed multiple hyperechoic masses. Abdominal contrast-enhanced CT scan and magnetic resonance imaging (MRI) showed multiple hypervascular masses compatible with metastatic tumors. No suspicious lesions were detected on examinations for malignancy in other organs. Distant metastases in cases of IPC with invasion are very rare. The potential of distant metastasis in IPC with invasion and the difficulty of evaluating invasive foci should be recognized. Careful evaluation of distant metastases is recommended.

Adenocarcinoma↗

PubMed2005

Progressive central nervous system metastases in responder patients for outside central nervous system metastases on trastuzumab-based therapy--report of two cases of refractory breast cancer.

We report two cases of central nervous system (CNS) metastases during systemic response to trastuzumab in combination with chemotherapy for refractory breast cancer. The patients responded to trastuzumab in combination with chemotherapy. During combination treatment, the patients developed cerebellar metastases. A follow-up computed tomography scan revealed that their diseases continued to respond outside the CNS. These cases suggest that the failure of trastuzumab to cross the blood-brain barrier may compromise its overall effectiveness and raises the possibility that CNS metastasis may become clinically more significant in patients receiving antibody-based therapies, including patients responding to therapy outside the CNS. Additionally, repeated stereotactic radiosurgery as gammaknife combination therapy synchronously with systematic trastuzumab-based therapy was useful for the treatment of metastatic breast carcinoma.

Adult↗

PubMed2005

[Surgical stress].

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Arachidonic Acids↗

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↗

PubMedDate not supplied

The spleen plays an immunosuppressive role in patients with gastric cancer: involvement of CD62L+ cells and TGF-beta.

CD62L is the human homologue of the murine lymphocyte homing receptor, mel-14. We investigated CD62L + cells in the spleen from patients with gastric cancer. Flow cytometric analysis revealed that CD62L + cells were decreased in the peripheral blood, but inversely increased in the spleen in parallel with disease progression in gastric cancer patients. The increased CD62L+ cells resided in the CD4+ suppressor-inducer phenotype, and the removal of CD62L+ cells from spleen cells resulted in a decrease of concanavalin-A-induced suppressor activity in vitro in one-way allogeneic mixed lymphocyte reaction. The CD62L+ cells included CD4+CD25+ regulatory T cells. The culture supernatant of CD62L + cells showed TGF-beta activity that permitted anchorage-independent growth of normal rat kidney (NRK) cells in a soft agar. TGF-beta activity was more significantly detectable in the splenic vein than in the peripheral blood, and TGF-beta mRNA was detectable in the spleen from advanced gastric cancer patients. These results suggest that CD62L+ cells migrate into the spleen with disease progression of gastric cancer and serve as suppressor-inducer cells with TGF-beta production to induce regulatory T cells, contributing to disease-associated immunosuppression in advanced gastric cancer patients.

Aged↗

PubMedDate not supplied

HER2-specific cytotoxic activity of lymphokine-activated killer cells in the presence of trastuzumab.

We investigated whether trastuzumab, a humanized anti-HER2 monoclonal antibody, could induce HER2-specific cytotoxic activity on lymphokine-activated killer (LAK) cells. Trastuzumab alone was not toxic to the HER2-positive breast cancer cell lines MDA-MB453 and ZR75-1, nor to the HER2-negative breast cancer cell lines MDA-MB468 and MCF-7. LAK cells, which were activated with 1000 U/ml IL-2 for 4 days (4-day LAK), showed cytotoxic activity against the MDA-MB453, ZR75-1 and MCF-7 cells, but not against MDA-MB468 cells. LAK cell cytotoxic activity against the HER2-positive breast cancer cell lines MDA-MB453 and ZR75-1 was significantly augmented in the presence of 10 nM trastuzumab, but that against the HER2-negative breast cancer cell lines MDA-MB468 and MCF-7 was not. The cytotoxic activity of LAK cells plus trastuzumab against the MDA-MB453 cells was significantly inhibited by the addition of cold MDA-MB453 cells or cold ZR75-1 cells, but not by addition of cold MDA-MB468 cells. Twenty-nine percent of the 4-day LAK cells were CD16+, and the cytotoxicity of LAK cells plus trastuzumab was abrogated with the anti-CD16 antibody treatment of the LAK cells in the cytotoxicity assay. Only 7% of the 10-day LAK cells were CD16+, and the 10-day LAK cells failed to exhibit cytotoxicity even with trastuzumab. These results suggest that HER2-specific cytotoxic activity, which is mediated by an antibody-dependent cellular cytotoxicity (ADCC) mechanism, can be induced on LAK cells by the addition of trastuzumab.

Antibodies, Monoclonal↗

PubMedDate not supplied

Feasibility study of adoptive immunotherapy for metastatic lung tumors using peptide-pulsed dendritic cell-activated killer (PDAK) cells.

We have established a novel culture system to generate effector lymphocytes designated as peptide-pulsed dendritic cell-activated killer (PDAK) cells using cultured dendritic cells (DCs), synthetic peptide, peripheral blood lymphocytes, and interleukin-2 plus immobilized anti-CD3 antibody. A feasibility study of an adoptive immunotherapy trial using PDAK cells was conducted on HLA-A2 and HLA-A24 cancer patients with antigen-positive lung metastasis that was defined by serological analysis or PCR analysis. Eleven patients with lung metastasis participated in the study: 6 with colorectal cancer, 2 with pancreatic cancer, 1 each with breast and lung cancer, and 1 with melanoma. The patients received either Muc-1, CEA, gpl00, Her-2 or SART-3-PDAK cells generated in vitro, intravenously in combination with 350,000 U IL-2 weekly for 9 weeks, together with a planned dose-escalation schedule of three transfers each of 1 x 10(7), 3 x 10(7) and 1 x 10(8) PDAK cells/kg for 6 patients, and with a uniform dose of 3 x 10(7) PDAK cells/kg for the remaining 5 patients. Peptide/HLA-specific cytotoxic activity and TCRVbeta gene usage of PDAK cells were analyzed. All transfers of PDAK cells, which showed peptide/HLA-specific lysis, were well-tolerated in all patients, and adverse effects (elevation of transaminase, fever, and headache) were observed primarily at grade 1, but in no case greater than grade 2. The generation of sufficient cells to treat the patients with 3 x 10(7) PDAK cells/kg was feasible using our culture system, but we were able to generate and administer the dose of 1 x 10(8) PDAK cells/kg in only one patient. One partial response (PR) of lung metastasis occurred in a pancreatic cancer patient who received 3 x 10(7) Muc-1-PDAK cells/kg. The cytolytic units of PDAK cells in this patient appeared to be substantially higher compared to those in PD patients. TCR gene usage analysis on PDAK cells revealed preferential usage of TCRVbeta segments. These results suggest that adoptive immunotherapy using PDAK cells for cancer patients with antigen-positive lung metastasis is safe and feasible, and tumor response should be examined in a future clinical trial

Adult↗

PubMedDate not supplied

Essential requirement of toll-like receptor 4 expression on CD11c+ cells for locoregional immunotherapy of malignant ascites using a streptococcal preparation OK-432.

Toll-like receptors (TLRs) are important molecules that stimulate the innate immunity in order to eradicate microbial pathogens, after which the adaptive immunity emerges. The involvement of TLRs in the action mechanism of OK-432, a bacterial preparation, was investigated in the locoregional treatment of malignant ascites from gastric cancer. The expression of TLRs in ascites cells was analyzed using reverse-transcription polymerase chain reaction specific for TLRs and by flow cytometry using anti-TLR2, -TLR4, -CD4, -CD8, and -CD11c antibodies. These measurements were compared with the locoregional response of OK-432 immunotherapy for malignant ascites, as well as TNF-alpha producing potential, which was measured by ELISA, of ascites cells stimulated in vitro with OK-432. It was observed that OK-432 immunotherapy for malignant ascites showed 8 positive (67%) and 4 negative responses with the tolerable adverse effects of fever elevation and abdominal pain. The TNF-alpha production of ascites cells by in vitro OK-432 stimulation was significantly higher in responder patients than in non-responders. The clinical responses were correlated with the expression of the TLR4 gene of ascites cells. The TNF-alpha-producing potential of ascites cells by in vitro OK-432 stimulation was dependent on the existence of a CD11c + TLR-4+ cell population in ascites cells. OK-432 was highly stimulatory for TNF-alpha production of ascites cells compared with other biological response modifiers of PSK and LEM. These results suggest that TLR-4 expression on ascites cells of a macrophage lineage is essential for ascites cells to produce TNF-alpha in relation to OK-432 stimulation and for subsequent positive clinical responses in locoregional immunotherapy using OK-432 for malignant ascites from gastric cancer.

Ascites↗