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Tsuyoshi Itoh

Publications and source records attributed to Tsuyoshi Itoh.

At least 37 records · Page 2Linked to original sources
PubMed2004

Evaluation of native valve-sparing aortic root reconstruction with direct imaging--reimplantation or remodeling?

BACKGROUND: Aortic root reimplantation and remodeling have been used to preserve the native aortic valve. However, direct observation of valve motions with these techniques has not been performed. METHODS: Mongrel dogs were studied. The beating heart model was created using modified Tyrode's solution. Normal aortic valves and aortic valves preserved with the remodeling or reimplantation procedure were observed with an endoscope, and behavior was recorded on a high-speed video (200 frames/s). The aortic valve orifice area was measured at 11 data points per beat. A predictable maximum valve orifice area was defined as an area encircled by the three commissures. A ratio of each aortic valve orifice area to the predictable maximum valve orifice area was calculated. The control group, the reimplantation group, and the remodeling group were compared. RESULTS: The preserved aortic valve with reimplantation showed bending and asymmetric motion. The ratio of aortic valve orifice area and predictable maximum valve orifice area in the reimplantation group was significantly smaller compared with the control and remodeling groups. CONCLUSIONS: The opening and closing behavior of the aortic valve preserved with the reimplantation procedure was impaired. It was speculated that the remodeling procedure may preserve more physiologic root function compared with the reimplantation procedure.

Animals↗
PubMed2004

Predictive factors for survival in surgically resected clinical IA peripheral adenocarcinoma of the lung.

BACKGROUND: Patients with clinical IA (C-IA) lung cancer have a 5-year survival rate of approximately 70% after surgical therapy alone. We attempted to clarify preoperative factors that are predictive for poor prognosis after surgery among patients diagnosed with C-IA adenocarcinoma of the lung. METHODS: Between 1994 and April 2002, 65 patients with C-IA adenocarcinoma of the lung underwent lobectomy + hilar and mediastinal node dissection. The chest computed tomography (CT) imaging and clinicopathologic records of the patients were examined. Tumors were subtyped into solid type or nonsolid type categories according to the component of ground glass opacity assessed by CT. Age, sex, serum carcinoembryonic antigen (CEA) level, histologic subtype (replacing versus nonreplacing), and tumor size were also analyzed. RESULTS: Solid type on CT and high serum CEA level (>or=4.0 ng/mL) were prognostic factors for poor outcome in univariate analyses (p < 0.05). Solid type on CT, high serum CEA level, and larger tumor size (> 20 mm) were significant (p < 0.05) prognostic factors for poor outcome in multivariate analyses. Solid type on CT and high serum CEA level were significant (p < 0.01) risk factors for lymph node involvement in both univariate and multivariate analyses. Furthermore, based on the factors of CT subtype, tumor size, and serum CEA level, the 5-year disease-free survival rate was 20.1% for patients with two of the three factors, and 21.2% even if they were assessed as pN0. Computed tomography subtype was strongly associated with histologic subtype (p < 0.0001). CONCLUSIONS: Solid type on CT (associated with histologic subtype such as nonreplacing type), tumor size larger than 20 mm, and high serum CEA concentration are important preoperative predictive factors for poor outcome after surgery for patients with C-IA lung adenocarcinoma.

Adenocarcinoma↗
PubMed2004

Heparinless cardiopulmonary bypass with argatroban in dogs.

OBJECTIVES: Systemic heparinization is usually required for cardiopulmonary bypass (CPB). However, problems such as heparin-induced thrombocytopenia, protamine shock, and antithrombin III deficiency exist related to CPB with heparinization. The aim of this study was to evaluate argatroban (ARG) as a substitute for heparin during CPB. METHODS: In the pilot study, blood samples were sequentially obtained from dogs with continuous infusion of ARG at a dose of 10 (n = 6), 20 (n = 6), or 30 (n = 6) microg/kg per min for 2 h without CPB. In the main study, dogs underwent CPB for 2 h with 10 (n = 6) or 30 (n = 6) microg/kg per min of ARG or with heparin with blood samples obtained sequentially. Thrombogenicity in each group was evaluated by observation of the blood-contacting surfaces of the CPB circuits with scanning electron microscopy (SEM). Evidence of thromboembolism in the dogs was also investigated in histological specimens of the kidney and spleen in addition to microscopic observation at autopsy. RESULTS: In the pilot study, the activated coagulation time (ACT) reached a maximum level dose-dependently after continuous infusion of ARG for 30 min. ACT returned to the baseline value within 60 min after the termination of continuous infusion. In the main study, CPB with 30 microg/kg per min of ARG achieved thrombin-antithrombin III complex (TAT) level similar to that achieved by CPB with heparin. Platelet count with 30 microg/kg per min of ARG tended to be higher than that with heparin or 10 microg/kg per min of ARG. The SEM appearance of blood-contacting surfaces of the CPB circuits after infusion with 30 microg/kg per min of ARG appeared to be similar to that after infusion with heparin. Depositions on the blood-contacting surfaces of the CPB circuits were also frequently observed with 10 microg/kg per min of ARG. CONCLUSIONS: Coagulability related to CPB was controlled by the appropriate ARG dosage without the use of heparin in dogs. ARG may be a substitute for heparin in CPB.

Animals↗
PubMed2004

Carcinoembryonic antigen as a predictive factor for postoperative tumor relapse in early-stage lung adenocarcinoma.

OBJECTIVES: To clarify the usefulness of measuring serum carcinoembryonic antigen (CEA) preoperatively to detect patients who will have a poor outcome after surgery, and who cannot be selected by conventional staging modalities. METHODS: One hundred patients with adenocarcinoma of the lung underwent standard surgical procedures between 1994 and April 2001 at our institution. Preoperative staging was assessed according to the TNM classification of the International Union Against Cancer. The associations between preoperative serum CEA level and the postoperative recurrence or lymph node metastasis were examined. The serum CEA level was classified into two groups according to concentration of CEA level: low (normal) CEA ( 5.0 ng/ml). RESULTS: The high CEA level was associated with tumor relapse (P=0.01). According to the preoperative staging, the increased CEA was associated with tumor relapse only in stage C-IA (P=0.001). Stage C-IB and more advanced stages did not show an association between increased CEA and tumor relapse. In C-IA, risk for lymph node involvement was significantly higher in the high CEA group (4/9; 44.4%) than in the low CEA group (6/47; 12.8%, P=0.03). Furthermore, the rate of tumor relapse in C-IA-pN0 was significantly higher in the high CEA group (4 of the 5, 80%) than in the low CEA group (9 of the 41, 22.0%, P=0.018). The 5-year disease-free survival rate for patients with a high serum CEA level (N=9) was 22.2%, and 75.0% for patients with a normal CEA (N=47) level (P=0.0004). CONCLUSIONS: Increased serum CEA is an important predictive factor for poor outcome after surgery in early-stage (C-IA) lung adenocarcinoma.

Adenocarcinoma↗
PubMed2004

Lung adenocarcinoma can be subtyped according to tumor dimension by computed tomography mediastinal-window setting. Additional size criteria for clinical T1 adenocarcinoma.

OBJECTIVE: We sought to verify that the size of the solid component, which can be evaluated using the computed tomography mediastinal-window setting, provides new criteria for CT classification of lung adenocarcinoma. METHODS: Between 1994 and September 2002, we examined 60 patients who were clinically classified with stage T1 adenocarcinoma of the lung and normal serum CEA, who underwent standard surgical procedures. Tumor maximum dimension was evaluated using two different CT-imaging settings: the lung window (lDmax), and the mediastinal window (mDmax). We analyzed the relationships between prognosis or lymph node involvement and tumor dimensions. RESULTS: The mDmax was a significant (OR 1.11, P=0.02) predictive factor for lymph node metastasis. However, lDmax was not significant (P=0.83). Age, gender, lDmax, mDmax, and lymph node involvement were analyzed as predictive factors for prognosis. In univariate analysis, mDmax and lymph node involvement were significant predictive factors for prognosis (OR 1.07, P=0.01; OR 2.56, P=0.04; respectively). In multivariate analysis, mDmax was a significant predictive factor for prognosis (OR 1.06, P=0.04). We then classified the C-T1 adenocarcinoma patients into three groups according to mDmax: T1a (< or =10 mm), T1b (from 11 to 20 mm), and T1c (from 21 to 30 mm). There was a significant difference between the three groups: the disease-free 5-year survivals were 93.3, 58.1, and 32.7%, respectively (P=0.01). CONCLUSIONS: The mDmax can give additional, useful prognostic data. This finding may provide new criteria for CT classification of lung adenocarcinoma.

Adenocarcinoma↗
PubMed2004

Ultrafiltration and alumina adsorption of micelles for the preconcentration of copper(II) in water.

Micellar-enhanced ultrafiltration was considered from the viewpoint of trace analysis, by taking copper(II) as an example. Copper(II) cations were collected electrostatically on micelles of sodium dodecyl sulfate, and separated from the mother liquor by ultrafiltration. However, the final solution contained a large amount of surfactant, which caused serious interference in the determination. This problem was overcome by using alumina adsorption, where negatively charged micelles were adsorbed on positively charged alumina particles and then recovered by conventional filtration. The copper was leached from the micelles with 4 mol l(-1) nitric acid, leaving the surfactant on the alumina. The proposed method was successfully applied to an analysis of certified reference water samples.

Journal Article↗
PubMed2004

Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen-derived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with metastatic gastrointestinal or lung adenocarcinomas.

We conducted a clinical study of cancer vaccine therapy with dendritic cells (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to assess the feasibility and efficacy of such therapy. Eighteen patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomas who were positive for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the patients' autologous monocyte-enriched fractions of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. The generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide (CEA652) and injected into the patients intradermally and subcutaneously every 2 weeks. Toxicity and clinical and immunological responses were closely monitored in each patient. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. Although no definite tumor shrinkage occurred in any patient, long-term stable disease or marked decreases in the serum CEA level were observed in some patients after therapy. Most of the patients in whom treatment was clinically effective showed a positive skin response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a positive in vitro CTL response to CEA652 peptide after therapy. We conclude that active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible treatment that is clinically effective in some patients with metastatic gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage further refinement and development of DC-based immunotherapy with HLA-A24-restricted CEA-derived peptide for refractory solid cancers that express CEA.

Adenocarcinoma↗
PubMed2004

Mobilization of peripheral blood stem cells (PBSCs) after etoposide, adriamycin and cisplatin therapy, and a multimodal cell therapy approach with PBSCs in advanced gastric cancer.

The EAP combination of etoposide (ETP), doxorubicin (ADM) and cisplatin (CDDP) has been reported to be highly active for advanced gastric cancer. However, it is associated with severe myelotoxicity, and its use has declined. We examined whether peripheral blood stem cells (PBSCs) could be mobilized during hematopoietic recovery after EAP, and assessed the possibility of using multimodal cell therapy with PBSCs for the treatment of advanced gastric cancer. Five men with advanced gastric adenocarcinoma were enrolled. All patients were chemotherapy-naïve. EAP (ETP, 360 mg/m2; ADM, 40 mg/m2; CDDP, 80 mg/m2) was given to each patient, and myelotoxicity was carefully monitored. Granulocyte colony-stimulating factor was administered after the neutrophil nadir, and PBSCs were collected by leukapheresis during hematopoietic recovery. The median nadir of the neutrophil count after EAP was 225/ml, occurring between day 17 and 20. Sufficient numbers of PBSCs [CD34(+) cells, CFU-GM] could be mobilized in 4/5 patients. A 45-year-old patient with extended lymph node metastasis received high-dose EAP with peripheral blood stem cell transplantation (PBSCT), followed by cancer vaccine therapy with dendritic cells (DCs), induced from cryopreserved PBSCs. Both high-dose EAP with PBSCT and DC-based immunotherapy was safely performed for the first time against gastric cancer. Although associated with severe myelotoxicity, EAP can mobilize sufficient numbers of PBSCs during hematopoietic recovery. Multimodal cell therapy combining high-dose chemotherapy with PBSCT and DC-based immunotherapy is feasible and can be a reasonable approach in advanced gastric cancer.

Adenocarcinoma↗
PubMed2004

Recognition of Epstein-Barr virus-associated gastric carcinoma cells by cytotoxic T lymphocytes induced in vitro with autologous lymphoblastoid cell line and LMP2-derived, HLA-A24-restricted 9-mer peptide.

Epstein-Barr virus (EBV) is associated with several types of malignancies including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma, and gastric carcinoma. Previous reports have suggested that EBV-related antigen-targeting immunotherapy is one of the promising approaches for the treatment of these malignancies other than gastric carcinoma. EBV-associated gastric carcinoma (EBVaGC) has been shown to express Epstein-Barr virus nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). In the present study, DNA and mRNA freshly isolated from tumors of patients with gastric cancer were subjected to polymerase chain reaction (PCR) using EBV-specific primers and reverse transcription (RT)-PCR specific for LMP2 transcripts. EBV-specific region was identified in genomic DNA isolated from cancerous tissues in 22% of gastric cancer patients. LMP2 mRNA was also detected in 3 out of these 5 DNA positive samples tested. To investigate the feasibility of specific immunotherapy for EBVaGC, we induced cytotoxic T lymphocytes (CTLs) from peripheral blood lymphocytes using two kinds of antigen-presenting cells (APCs) such as autologous lymphoblastoid cell line (LCL) and LMP2-derived peptide-pulsed dendritic cells (DCs). The cytotoxicity of these CTLs against peptide-pulsed targets was examined by standard 51Cr release assay and interferon (IFN)-gamma production assay. We further assessed the recognition of tumor cells endogenously expressing LMP2 by these T cells. T cells induced by peptide-loaded DCs and autologous LCL efficiently lysed peptide-pulsed targets. Furthermore, these T cells could recognize not only tumor cells transfected with LMP2, but also LMP2-positive gastric cancer cells which were successfully isolated and cultured from specimens obtained by surgery. Collectively, sensitization of peripheral blood lymphocytes with LMP2-derived peptide was able to induce CTL response against EBVaGC cells. Thus, EBVaGC is susceptible for the LMP2-targeting immunotherapy.

Aged↗
PubMed2003

Streptococcal preparation OK432 promotes functional maturation of human monocyte-derived dendritic cells.

Streptococcal preparation OK432 is an immunomodulatory agent extensively used as adjuvant therapy for gastric cancer in Japan. OK432 augments the cytotoxic activity of various effector cells such as lymphocytes, macrophages and (natural killer) NK cells and induces the production of multiple cytokines. Dendritic cells (DC) are professional antigen-presenting cells (APC) that can be used for cancer vaccine therapy. In the present study, we investigated the effect of OK432 on the activation of DC. Here we report that OK432 induced phenotypic and functional maturation of human monocyte-derived DC. In vitro culture of immature DC generated from adherent peripheral blood mononuclear cells (PBMC) using granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) with OK432 at various doses (0.01 to 0.1 KE/ml) for 2 days resulted in increased cell surface expression of CD80, CD83, CD86 and ICAM-1 in a dose-dependent manner. The expression of CD83, a selective marker of mature DC, on DC activated by OK432 (OK-DC) was maximally enhanced after 3 days of incubation. Assay of cytokine production in OK-DC after 2 days in culture revealed that OK432 was a strong inducer of IL-12 and interferon-gamma (IFN-gamma). OK432 efficiently augmented the primary allogeneic T-cell responses by DC. This distinct phenotypic profile and allostimulatory capacity of OK-DC was stable for at least 48 h of additional culture in the absence of any cytokines. Moreover, the antiviral cytotoxic T lymphocytes (CTL) response in vitro was also enhanced by the addition of OK432 to the cultures. These findings suggest that OK432 is a potent stimulator of DC, and that stimulated DC are strong inducers of the T helper 1 (Th1)-type response. We conclude that OK-DC are likely candidates for use as an adjuvant for DC-based cancer immunotherapy.

Antigen Presentation↗
PubMed2003

Coronary occlusion using bi-directionally stretched elastic sutures during off-pump coronary artery bypass grafting.

OBJECTIVE: Off-pump coronary artery bypass grafting may be partly invasive, particularly to the coronary endothelium that is snared. Efficacy of a simple technique to occlude a coronary artery with elastic sutures bi-directionally stretched just beneath the artery was evaluated. METHODS: Test subjects were eighteen adult mongrel dogs weighing 20-30 kg. After systemic heparinization (150 U/kg), the mid-left anterior descending artery (mid-LAD) was exposed with a stabilizer applied and snared using non-elastic sutures (n = 6) or elastic sutures (n = 6), or occluded with elastic sutures bi-directionally stretched (n = 6). The left internal thoracic artery (LITA) was anastomosed to the mid-LAD with humidified gas insufflation. After completion of the anastomosis, the mid-LAD was observed endoscopically through the LITA. The coronary endothelium was also observed by a scanning electron microscope (SEM) after perfusion fixation. RESULTS: Bleeding at the anastomotic site with the coronary artery occluded by bi-directionally stretched elastic sutures was observed. However, all anastomoses were done successfully with the aid of humidified gas insufflation. Coronary endoscope showed that the lumens snared with non-elastic sutures were collapsed with folds and often with clots. Coronary arteries snared with elastic sutures appeared similar to the arteries snared with non-elastic sutures endoscopically, but with less clots. In the case of coronary occlusion with bi-directionally stretched elastic sutures, the lumens were occluded in a flattened linear fashion without clots. SEM showed endothelial injuries with blood cells deposited when non-elastic sutures were used. When elastic sutures were used for snaring, endothelial injuries were ameliorated with less blood cells deposited, which were further decreased when elastic sutures were bi-directionally stretched. CONCLUSION: The coronary artery can be effectively occluded by bi-directionally stretched elastic sutures with minimal endothelial damage.

Animals↗
PubMed2003

Giant cell tumor of the rib.

We experienced a rare case of giant cell tumor (GCT) arising in the 5th rib involving the 5th vertebral body and transverse process. A 57-year-old man presented with a well-defined mass in the left thoracic cavity on chest x ray examination. Chest computed tomography showed a heterogeneous 7cm-diameter mass originating in the posterior segment of the left 5th rib. The tumor had spread to the 5th thoracic vertebra destroying the left half of the body and transverse process. Magnetic resonance imaging showed a heterogeneous-intensity mass involving the 4th to 6th ribs. A radical excision of the tumor followed by a 50 Gy radiotherapy was performed after embolization of the feeding arteries. The pathological diagnosis was a GCT. The patient remains well without evidence of recurrence for 6 years following surgery. The present case is only the 14th case of GCT arising in the rib to have been reported in Japan.

Bone Neoplasms↗
PubMed2003

Long-term results of coronary artery bypass grafting in patients with renal insufficiency.

BACKGROUND: There are few published studies on coronary artery bypass grafting in patients with renal insufficiency who are not on maintenance dialysis. No details of long-term results have been published. METHODS: This retrospective study focuses on 117 consecutive coronary artery bypass grafting patients with renal insufficiency, but who did not require dialysis (group B: preoperative serum creatinine level > or = 1.5 mg/dL). For comparison purposes, patients on maintenance dialysis (group C: 84 patients) and patients with normal renal function (group A: 794 patients; preoperative serum creatinine level < 1.0 mg/dL) were selected. RESULTS: Hospital mortality was 11% (13 of 117) in group B, 5.9% (5 of 84) in group C, and 1.6% (13 of 794) in group A, and between groups A and B, p < 0.0001, and between groups B and C, p = 0.24. Actuarial survival rates at 10 years, including all deaths, were 87%, 32%, and 29% in groups A, B and C, respectively, and between groups A and B, p < 0.009 and between groups B and C, p = 0.63. In 23 patients in group B, the bilateral internal thoracic artery was used. No cardiac deaths were observed in these patients during the mean follow-up time of 42 months (range, 1 to 128 months). Cox model analysis revealed nonuse of arterial grafting (p = 0.03; Hazards ratio 1.7) to be a statistically significant factor, and renal insufficiency (p < 0.0001; Hazards ratio 3.3) and maintenance dialysis (p < 0.0001; Hazards ratio 5.6) to be major independent risk factors for actuarial survival. CONCLUSIONS: Renal insufficiency was shown to be an independent risk factor for poor prognosis after coronary artery bypass grafting. However, aggressive use of arterial grafts, especially the internal thoracic artery, is recommended to improve late outcomes.

Aged↗
PubMed2003

Clinicopathological analysis of prognostic factors in clinical IA peripheral adenocarcinoma of the lung.

BACKGROUND: The clinical IA (C-IA) lung cancer patient shows a 5-year survival rate of approximately 70% after surgical therapy alone. We have tried to clarify the prognostic factors in C-IA adenocarcinoma of the lung to identify those candidates who might benefit from preoperative or postoperative adjuvant therapy. METHODS: Between 1994 and June 2001, 54 patients were diagnosed with C-IA adenocarcinoma of the lung and underwent lobectomy and hilar and mediastinal node dissection. The clinicopathological records of the patients were examined for age, gender, nodal status, tumor size, serum CEA level, and histologic subtype (replacing vs nonreplacing type). Localized bronchioloalveolar carcinoma (LBAC; noninvasive cancer) was excluded from this study. RESULTS: Nodal involvement, high serum CEA level (> or = 4.0 ng/mL), and nonreplacing type were significant (p < 0.05) prognostic factors for poor outcome in univariate analyses. Nodal involvement, larger tumor size (> or = 20 mm), and nonreplacing type were significant (p < 0.05) prognostic factors for poor outcome in multivariate analyses. High serum CEA level and nonreplacing type were significant (p < 0.01) risk factors for lymph node involvement both in univariate and multivariate analyses. Up to 71.5% of patients with both factors showed lymph node metastases. Furthermore, based on histologic subtype and tumor size, the 4-year survival rate was 33% for patients with both of these factors, and 34.3% even if they were pN0. CONCLUSIONS: C-IA patients, both with the larger tumor size (> or = 20 mm) and nonreplacing type, show poor outcome after surgery, and patients with both high serum CEA level and nonreplacing type are at high risk for lymph node metastases.

Adenocarcinoma↗
PubMed2003

Successful management of acute pulmonary embolism after surgery for lung cancer.

OBJECTIVE: Although many case reports of acute pulmonary embolism (APE) have been published, the literature dealing with the management of APE after resection of lung cancer is limited. This report describes seven cases of successful management of APE after surgery for lung cancer and discusses how to manage this problematic complication. METHODS: The medical charts of seven patients with APE after lobectomy and complete mediastinal lymphnode dissection were retrospectively reviewed. RESULTS: Six patients collapsed during their first attempt at walking after surgery in conjunction with a dramatic respiratory change. All these patients promptly underwent enhanced spiral computed tomography (CT) scanning. Bilateral clots were detected in all patients and one patient with a deep venous thrombus (DVT) in the femoral vein had a temporary inferior vena cava filter implanted. Non-surgical therapy was used for six patients: thrombolysis (systemic urokinase) and anticoagulant (heparin or argatroban) for four patients and only anticoagulant therapy started on the day after the operation using argatroban for two. There were no bleeding problems with these thrombolysis and/or anticoagulant therapies except in one case of hemorrhage induced by heparin usage on the day after the operation. None of the cases required allotransfusion in connection with these therapies. Thromboembolectomy was performed for one patient who was hemodynamically unstable due to massive embolism and primary atrial fibrillation. All patients were discharged from our hospital without major complications. CONCLUSIONS: Patients with pulmonary embolism after surgery for lung cancer can be treated aggressively with anticoagulants with/without fibrinolitics or even with pulmonary embolectomy on cardiopulmonary bypass, without excessive risk of bleeding complications. Enhanced spiral CT scanning was very helpful for making a simultaneous diagnosis of APE and DVT. The use of argatroban in conjunction with activated clotting time monitoring should be effective without causing bleeding problems during the early stages after pulmonary resection for lung cancer.

Acute Disease↗
PubMed2002

Immunotherapy of solid cancer using dendritic cells pulsed with the HLA-A24-restricted peptide of carcinoembryonic antigen.

Carcinoembryonic antigen (CEA), an oncofetal glycoprotein overexpressed in most gastrointestinal and lung cancers, is a candidate molecule for cancer immunotherapy. Recently, a CEA-derived 9-mer peptide, CEA652 (TYACFVSNL), has been identified as the epitope of cytotoxic T lymphocytes restricted with human leukocyte antigen (HLA)-A24, which is present in 60% of the Japanese population and in some Caucasians. The authors performed a clinical study of a vaccine using autologous dendritic cells (DCs) pulsed with CEA652 and adjuvant cytokines, natural human interferon alpha (nhuIFN-alpha), and natural human tumor necrosis factor alpha (nhuTNF-alpha), for the treatment of patients with CEA-expressing advanced metastatic malignancies. Ten HLA-A24 patients with advanced digestive tract or lung cancer were enrolled in the study to assess toxicity, tolerability and immune responses to the vaccine. DCs were generated from plastic adherent monocytes of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). Generated DCs showing an immature phenotype were loaded with CEA652 and injected into patients intradermally and subcutaneously with 50% of the dose administered by each route every 2 weeks for a total of ten vaccinations. The total dose of administered DCs ranged from 2.7x10(7)cells to 1.6x10(8)cells. Adjuvant cytokines, i.e., 1x10(6) U/body of nhuIFN-alpha and nhuTNF-alpha, were administered to patients twice a week during the vaccination period. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. In the delayed-type hypersensitivity (DTH) skin test, two patients showed a positive skin response to peptide-pulsed DCs after vaccination, although none of the patients tested positive prior to vaccination. In the two patients who showed a positive skin response disease remained stable for 6 and 9 months respectively. These results suggest that active immunization using DCs pulsed with CEA652 peptide in combination with the administration of adjuvant cytokines is a safe and feasible treatment procedure.

Adult↗