[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Mesohepatectomy with total resection of the caudate lobe and extrahepatic bile duct is sometimes performed for hilar cholangiocarcinoma or gallbladder carcinoma; however, only a few reports on mesohepatectomy with total caudate lobectomy of the liver for hepatocellular carcinoma are available. METHODS: A 71-year-old woman was preoperatively diagnosed with hepatocellular carcinoma in the central bisections (Couinaud's segments 4, 5, and 8) and the paracaval portion of the caudate lobe. Mesohepatectomy with total caudate lobectomy of the liver permitted the removal of tumors to provide a cancer-free raw surface of the liver. Mobilization of the caudate lobe is an important procedure in this surgery. Before the liver parenchyma was dissected, all short hepatic veins were ligated and divided from the left to the right side as the left lateral section was retracted to the right, and the caudate lobe branches of the portal vein and hepatic artery were ligated and divided. After the liver parenchymal dissection, both between the left lateral and medial sections and between the right anterior and posterior sections, the Glissonean branches of the caudate lobe were ligated and divided as the central bisections were anteriorly retracted. Finally, liver parenchymal dissection was performed between the caudate lobe and the right posterior section, which was along the right side of the inferior vena cava. RESULTS: The surgery time was 538 minutes and blood loss was 1,207 mL. No blood transfusions were required during or after surgery. The postoperative course was uncomplicated. The patient is still alive 25 months after hepatectomy. CONCLUSION: Although mesohepatectomy with total caudate lobectomy of the liver is technically more difficult than mesohepatectomy of the liver because the caudate lobe must be completely detached from the inferior vena cava and the hilar plate, it is a safe and effective treatment method in selected patients with hepatocellular carcinoma located at both the central bisections and the paracaval portion of the caudate lobe.
World Journal of Surgical Oncology 04/2013; 11(1):82. · 1.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatic resection is the only effective treatment for combined hepatocellular carcinoma and cholangiocarcinoma.
A 52-year-old man was preoperatively diagnosed with hepatocellular carcinoma in segment 2 with tumor thrombus in the segment 2 portal branch. Anatomical liver segmentectomy 2, including separation of the hepatic arteries, portal veins, and bile duct, enabled us to remove the tumor and portal thrombus completely. Modified selective hepatic vascular exclusion, which combines extrahepatic control of the left and middle hepatic veins with occlusion of left hemihepatic inflow, was used to reduce blood loss. A pathological examination revealed combined hepatocellular carcinoma and cholangiocarcinoma with tumor thrombus in the segment 2 portal branch. No postoperative liver failure occurred, and remnant liver function was adequate.
The separation method of the hepatic arteries, portal veins, and bile duct is safe and feasible for a liver cancer patient with portal vein tumor thrombus. Modified selective hepatic vascular exclusion was useful to control bleeding during liver transection. Anatomical liver segmentectomy 2 using these procedures should be considered for a patient with a liver tumor located at segment 2 arising from a damaged liver.
World Journal of Surgical Oncology 01/2012; 10:22. · 1.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colonic neuroendocrine cell carcinoma (NEC), which is a rare subtype of colon epithelial neoplasm, has been reported to show extremely aggressive characteristics with a 1-year survival rate of 20%. We report herein a resected case of NEC that manifested bacterial sepsis due to sigmoidovesical fistula. Staged surgery consisted of resecting the sigmoid colon and part of the bladder four weeks after construction of an ileostomy to alleviate septic shock. The resected specimen was histologically diagnosed as NEC invading the wall of the urinary bladder with metastasis to the regional lymph nodes. The patient underwent four cycles of FOLFOX after surgery for additional treatment of residual metastatic lymph nodes around the abdominal aorta diagnosed preoperatively. Although the patient showed stable disease measured by computed tomography scan for the first three months after surgery, he rejected additional chemotherapy thereafter, and died ten months after the initial admission due to progression of residual tumor in the urinary bladder as well as the lymph nodes. This is the first case report describing colonic NEC manifesting perforation into the urinary bladder. Although the optimal chemotherapeutic regimen for colonic NEC has not yet been established, FOLFOX may be one of the choices.
Case Reports in Gastroenterology 01/2010; 4(2):178-184.
[Show abstract][Hide abstract] ABSTRACT: Port-site herniation is a rare but potentially dangerous complication after laparoscopic surgery. Closure of port sites, especially those measuring 10 mm or more, has been recommended to avoid such an event.
We herein report the only case of a port site hernia among a series 52 consecutive cases of laparoscopy-assisted distal gastrectomy (LADG) carried out by our unit between July 2002 and March 2007. In this case the small bowel herniated and incarcerated through the port site on day 4 after LADG despite closure of the fascia. Initial manifestations experienced by the patient, possibly due to obstruction, and including mild abdominal pain and nausea, occurred on the third day postoperatively. The definitive diagnosis was made on day 4 based on symptoms related to leakage from the duodenal stump, which was considered to have developed after severe obstruction of the bowel. Re-operation for reduction of the incarcerated bowel and tube duodenostomy with peritoneal drainage were required to manage this complication.
We present this case report and review of literature to discuss further regarding methods of fascial closure after laparoscopic surgery.
[Show abstract][Hide abstract] ABSTRACT: We report a case of double cancer of the cystic duct and gallbladder associated with low junction of the cystic duct. A 73-year-old woman was admitted to the hospital complaining of upper abdominal pain. Endoscopic retrograde cholangiography showed a stenotic lesion in the lower common bile duct and no visualization of the cystic duct or gallbladder. Enhanced computed tomography revealed a heterogeneously enhanced tumorous lesion around the lower bile duct in the pancreatic head. A diagnosis of cancer arising from the cystic duct that entered the lower part of the common hepatic duct was made by intraductal ultrasonography, which showed an intraluminal protruding lesion in the cystic duct. Isolated gallbladder cancer was also diagnosed, by abdominal computed tomography. She underwent pancreaticoduodenectomy with dissection of regional lymph nodes. Histological examination revealed moderately differentiated adenocarcinoma of the cystic duct and well-differentiated adenocarcinoma of the gallbladder. Double cancer of the cystic duct and gallbladder is extremely rare, and this case also suggests a relationship between a low junction of the cystic duct and neoplasm in the biliary tract.
Journal of Hepato-Biliary-Pancreatic Surgery 02/2008; 15(3):338-43. · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current in vitro culture systems allow the generation of human dendritic progenitor cells (CFU-DCs). The aim of this study was to assess the effect of Flt3 ligand (FL) on the proliferation of human peripheral blood-derived myeloid CFU-DCs and their differentiation into more committed precursor cells (pDCs) using in vitro culture systems. Immunomagnetically separated CD34+ cells were cultured in serum-free, as well as in serum-containing, liquid suspension cultures to investigate the expansion and/or proliferation/differentiation of CFU-DCs, pDCs, and more mature dendritic cells (DCs). FACS-sorted CD34+Flt3+/- cells were cultured in methylcellulose to assay hematopoietic progenitors, including CFU-DCs. In the clonal cell culture supplemented with granulocyte/macrophage (GM) colony-stimulating factor (CSF), interleukin-4, and tumor necrosis factor alpha, the frequency of CFU-DCs was significantly higher in the CD34+Flt3+ fraction than in the CD34+Flt3- population, thus suggesting functional Flt3 expression on CFU-DCs. Serum-free suspension culture of CD34+ cells revealed the potent effect of FL on the expansion of CFU-DCs in synergy with GM-CSF and thrombopoietin (TPO). In addition, FL strongly induced the maturation of CFU-DCs into functional CD1a+ pDCs in serum-containing liquid suspension culture. Moreover, these FL-generated pDCs showed remarkable potential to differentiate into mature DCs with surface CD83/CD86 expression, which induced a distinct allogeneic T-cell response. These results clearly demonstrate that FL supports not only the proliferation of early hematopoietic progenitor cells, but also the maturation process of committed precursor cells along with the DC-lineage differentiation. Therefore, it is possible to develop a more efficient DC-based cancer immunotherapy using this specific cytokine combination, GM-CSF+TPO+FL in vitro in the near future.
International Journal of Oncology 07/2007; 30(6):1461-8. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have suggested that dendritic cell (DC)-based immunotherapy is one promising approach for the treatment of cancer. We previously studied the clinical toxicity, feasibility, and efficacy of cancer vaccine therapy with peptide-pulsed DCs. In that study, we used granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood monocytes as a cell source of DCs. However, previous investigations have suggested that G-CSF-mobilized peripheral blood monocytes produce reduced levels of proinflammatory cytokines such as interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. These T helper (Th)-1-type cytokines are thought to promote antitumor immune response. In this study, we assessed the functional abilities of DCs generated from G-CSF-mobilized monocytes obtained from 13 patients with CEA-positive advanced solid cancers. Peripheral blood mononuclear cells were obtained from leukapheresis products collected before and after systemic administration of G-CSF (subcutaneous administration of high-dose [5-10 microg/kg] human recombinant G-CSF for five consecutive days). In vitro cytokine production profiles after stimulation with lipopolysaccharide (LPS) were compared between monocytes with and without G-CSF mobilization. DCs generated from monocytes were also examined with respect to cytokine production and the capacity to induce peptide-specific T cell responses. Administration of G-CSF was found to efficiently mobilize peripheral blood monocytes. Although G-CSF-mobilized monocytes (G/Mo) less effectively produced Th-1-type cytokines than control monocytes (C/Mo), DCs generated from G/Mo restored the same level of IL-12 production as that seen in DCs generated from C/Mo. T cell induction assay using recall antigen peptide and phenotypic analyses also demonstrated that DCs generated from G/Mo retained characteristics identical to those generated from C/Mo. Our results suggest that G-CSF mobilization can be used to collect monocytes as a cell source for the generation of DCs for cancer immunotherapy. DCs generated in this fashion were pulsed with HLA-A24-restricted CEA epitope peptide and administered to patients safely; immunological responses were induced in some patients.
Cancer Immunology and Immunotherapy 04/2007; 56(3):381-9. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary malignant melanoma of the esophagus (PMME) is a very rare disease with an extremely poor prognosis. Surgery is currently considered its best treatment, while any other measures are ineffective. We studied the effect of active specific immunotherapy using monocyte-derived dendritic cells (DCs) pulsed with the epitope peptides of melanoma-associated antigens (MAGE-1, MAGE-3) in patients with PMME after surgery, for the first time. The patient received passive immunotherapy with lymphokine-activated killer cells concomitantly. Two HLA-A24-positive patients with PMME were treated. Both patients initially received radical esophagectomy with regional lymphadenectomy, followed by adjuvant chemotherapy with dacarbazine, nimustine, vincristine and interferon-alpha. In the case 1 patient, active specific immunotherapy was used to treat a large abdominal lymph node metastasis that became obvious 21 months after surgery. The disease remained stable for 5 months, and the patient survived for 12 months after the initiation of immunotherapy. In the case 2 patient, immunotherapy was tried as post-operative adjuvant treatment after adjuvant chemotherapy. There was no tumor recurrence for 16 months after the immunotherapy. As of 49 months after esophagectomy, the patient is still alive. In both patients, the ability of peripheral lymphocytes to produce IFN-gamma in vitro in response to peptide stimulation was significantly enhanced and delayed-type hypersensitivity skin test response to MAGE-3 peptide was turned positive after immunotherapy. In conclusion, active specific immunotherapy for PMME with the use of DCs and MAGE peptides was safe and capable of inducing peptide-specific immune responses. This case report warrants further clinical evaluation of this immunotherapy for PMME.
Japanese Journal of Clinical Oncology 03/2007; 37(2):140-5. · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Japanese Guide Lines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus (9th edn) give precedence to the location of the deepest tumor center rather than the range of tumor extension when determining regional lymph node grouping. We evaluated the validity of this recommendation.
The subjects were 49 patients with carcinomas of the distal thoracic esophagus and cardia who had undergone esophagectomy with three-field lymph node dissection. We measured variables defining tumor location, such as the distance from the esophagogastric junction (EGJ) to the proximal margin of the tumor (DJP), the distance from the EGJ to the distal margin of the tumor (DJD), and the distance from the EGJ to the deepest tumor center (DJC). To examine the relation of tumor location to lymph node metastasis in the proximal direction, the patients were divided into two groups according to the presence (14 patients) or absence (35 patients) of middle-upper mediastinal and/or cervical lymph node metastases. These two groups were compared with respect to the above variables. To analyze lymph node metastasis in the distal direction, the patients were also divided into two groups according to the presence (12 patients) or absence (37 patients) of distant abdominal lymph node metastases. These two groups were similarly compared with respect to the above variables.
DJP was significantly longer in the patients with middle-upper mediastinal and/or cervical lymph node metastases than in those without such metastases. Multiple logistic regression analysis showed that the DJP was a better predictor of middle-upper mediastinal and/or cervical lymph node metastases than was the DJC. The DJD was significantly longer in the patients with distant abdominal lymph node metastases. Multiple logistic regression analysis also showed that the DJD was a better predictor of distant abdominal lymph node metastases than was the DJC.
The range of tumor extension is a more reliable predictor of the risk of distant lymph node metastases than is the location of the deepest tumor center in esophageal carcinoma.
Japanese Journal of Clinical Oncology 01/2007; 36(12):775-82. · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immune responses are frequently depressed in patients with cancer. One of the reasons for a poor immune response is the presence of increased levels of immunosuppressive substances associated with tumor growth. Transforming growth factor-beta (TGF-beta), a representative immunosuppressive cytokine, plays various roles in the progression of cancer. To remove immunosuppressive substances from tumor-bearing hosts, we developed an immunosuppressive substance adsorption (ISA) column for direct hemoperfusion (DHP) treatment. It is filled with extra-fine fibers that can adsorb TGF-beta. In this study, we investigated the effects of this DHP treatment on serum levels and activities of TGF-beta, cellular immune responses, and anti-tumor effects in KDH-8 (TGF-beta-producing hepatocellular carcinoma cell line)-bearing rats. We further studied the ability of ISA fibers to adsorb tumor-associated immunosuppressive cytokines [TGF-beta, interleukin (IL)-6 and vascular endothelial growth factor (VEGF)] in samples of body fluids obtained from patients with metastatic cancer. DHP treatment decreased serum levels and activities of TGF-beta in tumor-bearing rats and restored T lymphocyte response to mitogen. Tumor growth in rats treated by DHP was significantly slower than that in untreated rats. The survival time of treated rats was significantly longer than that of untreated rats. The concentrations of TGF-beta, IL-6, and VEGF in the samples of human body fluids were decreased markedly by in vitro treatment with ISA fibers. These results suggest that DHP treatment with an ISA column, which removes TGF-beta and other immunosuppressive substances from the sera of tumor-bearing hosts, is potentially a new immunotherapeutic strategy for cancer.
[Show abstract][Hide abstract] ABSTRACT: Three-field lymph node dissection has been widely used to treat thoracic esophageal cancer, but is very invasive and can cause serious complications. Whether cervical lymph node dissection should be performed in all patients with thoracic esophageal cancer remains controversial. We pathologically examined the recurrent nerve lymph nodes during surgery in patients with thoracic esophageal cancer to determine the presence or absence of lymph node involvement. In patients without recurrent nerve nodal involvement, cervical lymph node dissection was not performed. Treatment outcomes were analyzed to evaluate whether intraoperative pathological investigation was a useful procedure. Among 71 patients with thoracic esophageal cancer who underwent 3-field lymph node dissection, the rate of cervical lymph node metastasis was 40.9% in patients with recurrent nerve nodal metastasis on intraoperative pathological investigation, as compared with 10.2% in patients without recurrent nerve nodal metastasis (p=0.007). Multiple logistic-regression analysis showed that recurrent nerve nodal metastasis was a strong predictor of cervical lymph node metastasis (odds ratio, 2.98; 95% confidence interval, 1.139-7.775; p=0.03). Among 41 patients who underwent intraoperative pathological investigation, 10 had recurrent nerve nodal metastasis and underwent cervical lymph node dissection. Two of these patients had histological evidence of cervical lymph node metastasis. The remaining 31 patients had no recurrent nerve nodal metastasis on intraoperative pathological examination and therefore did not receive cervical lymph node dissection. None of these patients had cervical lymph node recurrence on follow-up. We compared patients who underwent intraoperative pathological investigation with those who underwent conventional 3-field lymph node dissection (without performing intraoperative pathological investigation). The rates of cervical lymph node recurrence were similar among the groups (2.6% vs. 6.7%), but the 3-year survival rate was significantly higher in the patients who underwent intraoperative pathological dissection (83.3%) than in those who underwent 3-field dissection (57.2%; p<0.05). Although this was a retrospective study, our results suggest that outcomes of patients undergoing cervical lymph node dissection according to the results of intraoperative pathological investigation are at least as good as those in patients undergoing 3-field lymph node dissection. We conclude that intraoperative pathological investigation of recurrent nerve nodal metastasis is useful for determining whether cervical lymph node dissection should be performed in patients with thoracic esophageal cancer.
[Show abstract][Hide abstract] ABSTRACT: Recently, dendritic cells (DCs) and DC-tumor cell hybrids (DC-tumor hybrids) have been used for cancer vaccine therapy in a clinical trial. DC-tumor hybrids combine the potent antigen-presenting capacity of DCs with the ability to present all tumor antigens expressed on tumor cells to T cells. We used DC-tumor hybrids as stimulator cells to induce tumor-specific cytotoxic T lymphocytes (CTLs) in vitro. DC-tumor hybrids were generated from human monocyte-derived DCs and human cancer-cell lines (GT3TKB, lung cancer; GCIY, gastric cancer) by our newly developed electrofusion technique, established and refined with the use of mouse cells. To evaluate the capacity of DC-tumor hybrids generated by our method to induce tumor antigen-specific CTLs, we performed a cytotoxic assay and an interferon-gamma release assay using CD8-dominant effector lymphocytes induced by them. DC-tumor hybrids more effectively induced tumor-specific primary T-cell response than did stimulation with DCs co-cultured with irradiated tumor cells overnight, irradiated tumor cells alone, or a mixture of DCs and irradiated tumor cells. DC-tumor hybrids were generated at a high fusion rate by our electrofusion technique. When CTLs were induced by DC-tumor hybrids in vitro, the high fusion rate did not contribute to the induction of CTLs with increased tumor-specific cytotoxicity. The addition of interleukin-12 to the culture medium did not augment the cytotoxicity of CTLs. Overall, our results suggest that DC-tumor hybrids effectively induce human tumor-specific CTLs and may thus be applicable for clinical trials of adoptive immunotherapy.
International Journal of Oncology 10/2006; 29(3):531-9. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S-1 is an oral formulation combining tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. We examined whether Oxo reduces the immunosuppression induced by 5-fluorouracil (5-FU) in the rat. The body weight of rats treated with S-1 (FT + CDHP + Oxo) for seven consecutive days was significantly higher than that of rats treated with a combination of FT plus CDHP (FT + CDHP) for a similar period. The number of peripheral leukocytes was significantly higher in the S-1-treated rats (S-1 group) than that in the FT + CDHP-treated rats (FT + CDHP group). There was no apparent difference between the two treated groups in phenotypic changes of CD3-, CD45-, CD4-, or CD8-positive cells from the spleen or mesenteric lymph nodes. However, the natural killer activities of both spleen cells and mesenteric lymph node cells were significantly higher in the S-1 group than in the FT + CDHP group. Interleukin (IL)-2 production by spleen cells stimulated with concanavalin A was significantly lower in the FT + CDHP group than in the S-1 group. Although IL-2 production by mesenteric lymph node cells in the S-1 group was lower than that in untreated rats, it was higher than that in the FT + CDHP group. These findings suggest that Oxo in S-1 may reduce the suppression of antitumor immunity induced by 5-FU.
Cancer Chemotherapy and Pharmacology 09/2006; 58(2):183-8. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) have been shown to be potent in inducing cytotoxic T cell (CTL) response leading to the efficient anti-tumor effect in active immunotherapy. Myeloid DCs are conventionally generated from human peripheral blood monocytes in the presence of interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Streptococcal preparation OK-432, which is known to be a multiple cytokine inducer, has been extensively studied as to its maturation effects on immature DCs using an in vitro culture system. The purpose of this study was to examine whether it could be possible to generate mature DCs directly from peripheral monocytes using OK-432. We specifically focused on the possibility that recombinant cytokines, which are considered to be essential for in vitro DC generation, could be substituted by OK-432. Human peripheral monocytes, which were obtained from patients with advanced cancer, were cultured with IL-4 and OK-432 for 7 days. Cultured cells were compared with DCs generated in the presence of IL-4 and GM-CSF with or without OK-432 with regard to the surface phenotype as well as the antigen-presenting capacity. As a result, the culture of monocytes in the presence of IL-4 followed by the addition of OK-432 on day 4 (IL-4/OK-DC) induced cells with a fully mature DC phenotype. Functional assays also demonstrated that IL-4/OK-DCs had a strong antigen-presenting capacity determined by their enhanced antigen-specific CTL response and exerted a Th1-type T cell response which is critical for the induction of anti-tumor response. In conclusion, human peripheral blood monocytes cultured in the presence of IL-4 and OK-432 without exogenous GM-CSF demonstrated a fully mature DC phenotype and strong antigen-presenting capacity. This one-step culture protocol allows us to generate fully mature DCs directly from monocytes in 7 days and thus, this protocol can be applicable for DC-based anti-tumor immunotherapy.
International Journal of Oncology 07/2006; 28(6):1481-9. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The patients with advanced cancer often lose their anti-tumor immune responses due to the increase of some immunosuppressive substances in the blood, such as cytokines and proteins derived from cancer cells or immune cells. We developed the adsorption fiber in transforming growth factor (TGF)-beta for the treatment to remove immunosuppressive substances and investigated the effects of direct hemoperfusion using the filtration column filled with this adsorption fiber in tumor-bearing rats. On day 0, KDH-8 tumor cells (1 x 10(6) cells/rat) were implanted subcutaneously into the back of WKAH/Hkm rats. On day 21 after tumor implantation, the rats underwent the direct hemoperfusion with this filtration column for 60 minutes. On day 28, the rats were sacrificed and the natural killer (NK) activities of their spleen cells were examined. As a result, the rats that underwent this treatment showed a significant increase in their NK activities compared with those of rats who underwent direct hemoperfusion with an empty column or had no treatment. Therefore, we indicated the possibility of a new immunotherapy technique against cancer using a direct hemoperfusion column filled with an adsorption fiber for immunosuppressive substances.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2005; 32(11):1583-5.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
International Journal of Oncology 05/2004; 24(4):909-17. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Cancer Immunology and Immunotherapy 05/2003; 52(4):207-14. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Cancer Immunology and Immunotherapy 05/2002; 51(2):99-106. · 3.64 Impact Factor