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ABSTRACT: Lentinula edodes mycelia extract (L.E.M.) is extensively utilized as an herbal medicine. However, its safety and effectiveness have not yet been scientifically verified. In this study, we investigated its safety and its influence on quality of life (QOL) and the immune response in patients undergoing cancer chemotherapy. Seven patients were studied in total. The patients were undergoing postoperative adjuvant chemotherapy for breast cancer (n = 3) or gastrointestinal cancer (n = 2), or were receiving chemotherapy to prevent recurrence of gastrointestinal cancer (n = 2). The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of L.E.M. Adverse events and changes in the QOL score, lymphocyte subpopulations, lymphocyte activity and serum immune indices were evaluated during the study period. No adverse events attributable to L.E.M. were observed. Compared to the pre-chemotherapy state, no changes in QOL or immune parameters were noted after the first chemotherapy course. In contrast, following the second course of combined therapy, improvements were noted in QOL (p < 0.05), NK cell activity (p < 0.05) and immunosuppressive acidic protein (IAP) (p < 0.01) levels. Although a future large-scale investigation is necessary to confirm these results, these data suggest that the concomitant of L.E.M. with chemotherapy is safe and improves the QOL and immune function of patients undergoing chemotherapy.
The American Journal of Chinese Medicine 01/2011; 39(3):451-9. · 1.98 Impact Factor
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ABSTRACT: The patient was an 89-year-old male who consulted our hospital with a complaint of black stools. He had undergone gastrectomy and Roux-en Y reconstruction. Upper digestive tract endoscopy revealed a flat plate-like ulcer in the jejunum on the anal side of the gastrojejunostomy site. Biopsy findings suggested undifferentiated adenocarcinoma. Computed tomography (CT) showed cervical, mediastinal, and intraperitoneal lymph node swelling, suggesting metastasis. Extensive lymph node metastasis made curative resection impossible, and symptoms such as perforation/stenosis were absent. Therefore, surgery was not performed, and systemic hemotherapy with S-1 (80 mg/body/day) was administered. We repeated 2-week administration and 1-week discontinuation per course. After the end of the second course, upper digestive tract endoscopy revealed cicatrization of the ulcer, and CT showed a marked decrease in the lymph node size; a complete response (CR) was achieved. During the 7-month follow-up after the initial consultation (7 courses of S-1 therapy in all), there has been no exacerbation, and the quality of life (QOL) has been maintained.
Gan to kagaku ryoho. Cancer & chemotherapy 05/2010; 37(5):927-30.
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ABSTRACT: The safety and efficacy of docetaxel plus S-1 combination chemotherapy as a first-line treatment in patients with advanced or recurrent gastric cancer was verified retrospectively.
Eighteen patients with advanced or recurrent gastric cancer were enrolled. The regimen used was intravenous docetaxel, 40 mg/m(2), on day 1 and oral S-1, 80 mg/m(2)/day, on days 1-14 every three weeks.
In total 101 cycles were administered. One and 11 patients achieved complete and partial responses, while six and zero patients showed stable and progressive disease, respectively. The median time to progression (TTP) and median overall survival were 7.0 and 14.3 months, respectively. Neutropenia was the most common grade 3/4 hematological toxicity. Nausea and stomatitis were the most common grade 3 nonhematological toxicities. No treatment-related death was observed.
Docetaxel plus S-1 combination is an active and tolerable regimen as a first-line treatment in patients with advanced or recurrent gastric cancer.
Anticancer research 08/2009; 29(7):2775-9. · 1.73 Impact Factor
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ABSTRACT: Abstract After the discovery of interIeukin-2 (IL-2), lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and cytotoxic T lymphocytes (CTLs) sensitized with the mixed lymphocyte-tumor culture (MLTC) system have been conducted in adoptive immunotherapy (AIT) trials during past 15 years. Although the overall response rate of tumor shrinkage was marginal (9%), locoregional administration of TILs for malignant effusions was effective (77%) for a decrease or disappearance of the effusions even in terminally-ill patients, resulting in an improvement of QOL. Recent advances for molecular understanding of antigen presentation and recognition have promoted us to enhance the efficacy of AIT by using cultured dendritic cells (DCs) for generating antigen-specific CTLs in vitro. The peptide-pulsed DC-activated killer (PDAK) cells showed tumor recognition against antigen-expressing cells, and were efficiently propagated with the IL-2 plus immobilized anti-CD3 antibody (IL-2/CD3) culture system. Clinical trials using PDAK cells against patients with lung metastases are now progressed, in which peptides suitable for generating CTLs were chosen in individual patients using the method designated as host-oriented peptide evaluation (HPOE) approach. Moreover, DCs were introduced with tumor-derived RNA, which was amplified with the T7 promoter system, and then were used for stimulating lymphocytes. The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of ATT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer. Thus, more understanding of antigen-presentation and -recognition mechanisms and immune regulation systems may promote clinical applications of AIT to establish a novel modality of cancer treatment.
Human Cell 10/2008; 16(4):183 - 189. · 1.27 Impact Factor
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Yoshinori Yamashita,
Kazuhiko Kataoka,
Teruyoshi Ishida,
Motoki Matsuura,
Noritomo Seno,
Hidenori Mukaida, Eiji Miyahara,
Yoshihiro Miyata,
Riki Okita,
Katsuhiko Shimizu,
Masanobu Watari,
Tsuneo Okumichi,
Morihito Okada
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ABSTRACT: Recent clinical trials have shown significant survival benefits from postoperative adjuvant therapy for respectable nonsmall cell lung cancer (NSCLC). However, evaluation of adjuvant chemotherapy with carboplatin combination is still uncertain. The purpose of the study was to test the feasibility of adjuvant chemotherapy with carboplatin and separate weekly paclitaxel after complete resection of pStage IB, II, IIIA NSCLC in a multicenter study.
The study was conducted from 2001 to 2006 in the outpatient setting. A total of 61 patients were enrolled. Patients received adjuvant chemotherapy with 4 cycles of carboplatin (AUC 5) on day 1 and paclitaxel (70 mg/m) on day 1, 8, and 15 every 4 weeks. Primary endpoints were toxicity and chemotherapy compliance. Secondary endpoints were disease-free survival and overall survival.
More than 65% of eligible patients had pStage IIIA. The median number of chemotherapy cycles was 4 (range 1-4). Grade 3 or 4 toxicities of neutropenia were 34% (grade 4: 2%). Other hematologic adverse effects were extremely less frequent. Regarding the nonhematologic adverse effect, hair loss was frequent; however, peripheral neuralgia was less frequent. Treatment-related death was not registered. During median follow-up of 21 months, 24 patients developed recurrent disease. Estimated disease-free survival and overall survival at 2 years was 51.2% and 84.6%, respectively.
Postoperative carboplatin and weekly paclitaxel showed favorable feasibility and acceptable toxicity in comparison with the cisplatin-containing regimen. Consequently, it is desirable that this regimen would be validated in a phase III clinical trial for NSCLC after curative resection.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2008; 3(6):612-6. · 4.55 Impact Factor
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ABSTRACT: Recently, several randomized trials have shown that postoperative adjuvant treatment improves survival among patients with completely resected non-small cell lung cancer (NSCLC). Platinum-based chemotherapy has been reported to be effective for patients with postoperative stage II to IIIA.
In the present study, 5 patients with completely resected stage IIB and IIIA received carboplatin AUC 4 on day 1 and gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks for six cycles as adjuvant chemotherapy.
No early or toxic deaths were observed. All patients were administered 6 cycles completely and safely. Three patients had grade 3 neutropenia and three had grade 2 thrombocytopenia. One patient had grade 3 neutropenia on day 8 in the 2nd and 3rd cycle, and the medications were postponed for a week. Non-hematological toxicity including alopecia and neuropathy were not found.
In the present study, the combination of carboplatin and gemcitabine has been a safe and feasible regimen in adjuvant therapy for stage II and IIIA NSCLC.
Gan to kagaku ryoho. Cancer & chemotherapy 04/2008; 35(3):483-5.
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ABSTRACT: In our hospital, beginning in April 2005, chemotherapy for non-curative advanced or recurrent gastric cancer was integrated, and 9 regimens including 6 combination therapies were prepared. First-line chemotherapy mainly focusing on TS-1 plus docetaxel combination therapy(S-1+DOC)was done. Second-line and subsequent chemotherapy treatments were chosen by the doctor in charge. 78.6% of second-line chemotherapy was monotherapy. Median survival time(MST)since first-line chemotherapy was 15.6 months, and 1-year survival rate since first-line chemotherapy was 65.0%. MST since the start of first-line S-1+DOC was over 16.4 months, and 1-year survival rate since this therapy start was 69.0%. The good results were ascribed to following: 1. good response rate(30.4%), prolonged time to progression(TTP)(6.1 months), and good control against adverse events at first-line chemotherapy; 2. good shift rate of second-line chemotherapy from the first-line one(82.4%); and 3. good disease control rate(78.6%), prolonged TTP(7.0 months), and good control against adverse events at second-line chemotherapy. In patients with peritoneal metastasis, however, despite the prolonged TTP of 8.7 months by first-line chemotherapy, MST since first-line chemotherapy was poor at 11.1 months. Thus, improvement of second-line or subsequent chemotherapy is warranted.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2008; 35(1):55-60.
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ABSTRACT: FOLFOX regimens were administered to 14 patients with unresectable advanced or recurrent colorectal cancer from 1 to 9 cycles (median 5 cycles). In our patient characteristics, 10 patients had previous chemotherapies, 3 patients showed performance status 3. The response rate was 21%, and median time to progression was 5.0 months. Frequency of grade 3/4 adverse effect was 57% in neutropenia, 36% in leucopenia, 36% in thrombocytopenia, and 7% in allergic reaction. Only 64% patients could complete the treatment, for these adverse events brought treatment failure at 3-6 cycles. Median relative dose-intensity was 80-90% during 1-4 cycles, but about 50% after 5 cycles for these adverse events. No patient had grade 3 neurologic toxicity,because no one was administered over 10 cycles. FOLFOX regimens showed good anti-tumor effects but poor tolerability after 5-6 cycles in our patients.
Gan to kagaku ryoho. Cancer & chemotherapy 05/2007; 34(4):573-7.
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ABSTRACT: 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.
International Journal of Oncology 05/2004; 24(4):959-66. · 2.40 Impact Factor
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ABSTRACT: After the discovery of interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and cytotoxic T lymphocytes (CTLs) sensitized with the mixed lymphocyte-tumor culture (MLTC) system have been conducted in adoptive immunotherapy (AIT) trials during past 15 years. Although the overall response rate of tumor shrinkage was marginal (9%), locoregional administration of TILs for malignant effusions was effective (77%) for a decrease or disappearance of the effusions even in terminally-ill patients, resulting in an improvement of QOL. Recent advances for molecular understanding of antigen presentation and recognition have promoted us to enhance the efficacy of AIT by using cultured dendritic cells (DCs) for generating antigen-specific CTLs in vitro. The peptide-pulsed DC-activated killer (PDAK) cells showed tumor recognition against antigen-expressing cells, and were efficiently propagated with the IL2 plus immobilized anti-CD3 antibody (IL-2/CD3) culture system. Clinical trials using PDAK cells against patients with lung metastases are now progressed, in which peptides suitable for generating CTLs were chosen in individual patients using the method designated as host-oriented peptide evaluation (HPOE) approach. Moreover, DCs were introduced with tumor-derived RNA, which was amplified with the T7 promoter system, and then were used for stimulating lymphocytes. The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of AIT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer. Thus, more understanding of antigen-presentation and -recognition mechanisms and immune regulation systems may promote clinical applications of AIT to establish a novel modality of cancer treatment.
Human Cell 01/2004; 16(4):183-9. · 1.27 Impact Factor
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ABSTRACT: In induction of autologous tumor-reactive antigen (TRA) specific cytotoxic T lymphocytes (CTLs) using antigenic peptides and cultured dendritic cells (DCs), identification of the adequate tumor antigens and HLA typing of individuals are required. These restrictions have promoted the use of tumor cells themselves, including tumor cell lysates and tumor cell-DC fusion cells. However, it is very difficult to obtain enough tumor cells for treatment in the clinical setting. We have studied the use of RNA derived from tiny tumor cells. RNA was reverse-transcribed into cDNA, after which T7-amplification and in vitro transcription were carried out. The amplified RNA was successfully electroporated into DCs, and polyclonal polyspecific CTLs could be generated. EBV transformed B cells were also good candidates to be electroporated with the RNA. This suggests that tumor RNA amplification followed by introduction into DCs or EBV transformed B cells is a feasible and practical method to prepare potent APCs.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2003; 30(11):1813-6.
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ABSTRACT: Tumor-reactive effector lymphocytes were generated using tumor-derived amplified RNA and cultured dendritic cells (DC). Tumor RNAs were extracted from gastric cancer cell line MKN45 or cancer cells of malignant effusions, and were processed with T7 amplification. DCs were induced from an adherent cell population of peripheral blood mononuclear cells (PBMCs) with GM-CSF and IL-4. Tumor-RNA was introduced into DCs using electroporation. Effector cells were generated by stimulating a non-adherent fraction of PBMCs with tumor RNA-introduced DCs. It was observed that milligram RNA could efficiently be amplified from microgram RNA. The effector cells, designated as tumor-RNA-introduced DC-activated killer (TRiDAK) cells, showed IFN-gamma spots in a tumor-specific manner when examined using ELISPOT analysis, and demonstrated cytotoxic activities against tumor cells from which RNA was extracted. TRiDAK cells produced more tumor-specific IFN-gamma spots when stimulated repeatedly. These results suggest that TRiDAK cells are practical and may be effective lymphocytes for adoptive cancer immunotherapy.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2003; 30(11):1809-12.
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ABSTRACT: We investigated the induction of cytotoxic T lymphocytes (CTLs) specific for squamous cell carcinoma antigen SART-1 from the peripheral blood mononuclear cells (PBMCs) of an HLA-A24 healthy donor by in vitro stimulation with dendritic cells (DCs) pulsed with the antigenic peptide. Effector cells, designated as <peptide-pulsed dendritic cell-activated killer (PDAK)> cells, exhibited potent cytotoxic activity against target cells in a SART-1-specific and HLA-restricted manner. T cell receptor (TCR) gene usage of the SART-1 PDAK cells analyzed by reverse transcribed-polymerase chain reaction (RT-PCR) and Southern blot analysis showed oligoclonal usage, including TCRVbeta18, which was indicated by blocking assay to be responsible for antigen recognition and killing. Single strand conformation polymorphism (SSCP) analysis revealed clonotypic bands of the TCRVbeta18. The PCR product of the TCRVbeta18 was sequenced and complementarity determining region (CDR) 3 was determined. RT-PCR analysis using this CDR3 sequence as a primer showed, as expected, a positive band of about 30 bp smaller than shown on regular PCR analysis. This clonotypic PCR demonstrated an increasing density of PCR bands in the SART-1 PDAK cells during stimulation with SART-1 peptide plus DCs. It is suggested that clonotypic PCR using the TCR-CDR3 sequence may be useful in assessing the precursor frequency of CTLs reactive with the SART-1 peptide in vivo.
Oncology Reports 9(3):599-605. · 1.84 Impact Factor
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ABSTRACT: We have established a practical system for generating antitumor effector lymphocytes using the tumor antigen peptide CEA and cultured dendritic cells (DCs), and have also characterized effector cells. DCs were induced from the adherent cell population of autologous peripheral blood mononuclear cells (PBMCs) obtained from HLA-A0201 normal or tumor-bearing donors using IL-4 and GM-CSF. The cultured DCs were shown to express class I, class II, CD80 and CD86 molecules. The PBMCs were stimulated for 7 days with the DCs pulsed with the HLA-A0201-restricted CEA peptide CEA9 671 and then expanded in an anti-CD3 antibody (1 microgram/ml)-coated flask in the presence of a 80 U/ml IL-2 (IL-2/CD3 system). The effector cells, which were designated as CEA peptide-pulsed dendritic cell-activated killer (CEA-PDAK) cells, were preferentially CD3+CD8+, and capable of killing T2 cells pulsed with CEA peptide but not T2 cells alone. The CA-PDAK cells also lysed the gastric cancer cell line KATO III (HLA-A0201, CEA (+)), but not the WiDr (HLA-A2402, CEA(+)) cells. The cytotoxicity was abrogated when the CEA-PDAK cells were treated with anti-TCR alpha beta antibody or when the target cells were treated with the anti-class I antibody prior to the cytotoxicity assay. The CEA-PDAK cells exerted their cytotoxic activity even in the presence of a high amount of CEA protein at the effector phase, which mimicked the clinical setting. The CEA-PDAK cells showed approximately a hundred-fold expansion in total cell numbers yielded without any loss of the specific lysis, when stimulated with the IL-2/CD3 system compared to those stimulated with IL-2 alone. The TCR V beta gene analysis for the CEA-PDAK cells, conducted by means of RT-PCR-Southern blotting, demonstrated oligoclonal expression of TCR beta 7 and 12, and the latter was shown to be responsible for the killing activity. SSCP analysis indicated the clonotype of the TCR V beta 12 gene, indicating a selective expansion of lymphocytes bearing a limited TCR variable region by the stimulation with CEA peptide-pulsed DCs. Taken together, the effector lymphocytes reactive with the CEA antigen can be generated from PBMCs with the antigenic CEA peptide and cultured DCs. The IL-2/CD3 system is effective and practical in activating the effector cells for the clinical use of CEA-PDAK cells. Adoptive immunotherapy using this system may be promising for treating CEA-expressing tumors.
Anticancer research 22(5):2597-606. · 1.73 Impact Factor
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ABSTRACT: The aim of this study was the screening of gastrointestinal (GI) hormones release as possible sensitive tumor markers. The subjects were eight patients with carcinoma of the lung compared with nine healthy controls. Six kinds of GI hormones were measured by the specific radioimmunoassay. It was evaluated by fasting level (F), increased integrated responses (IIR60, IIR180 pmol/l/min) and total integrated responses (TIR60, TIR180 pmol/l/min) after a meal. The data were analyzed by the Student's t-test. The F of pancreatic polypeptide (PP) was significantly higher in patients than that in healthy controls (24.4 vs. 12.3 pmol/l, p = 0.002). Consequently, the sensitivity was 75% (6 out of 8) and specificity was 100% (9 out of 9). Almost all parameters of IIR60, IIR180, TIR60 and TIR180 in PP and peptide YY were significantly higher in patients than in healthy controls (p value: 0.00020-0.021). The other four kinds of hormones showed similar results to the healthy controls. These results seem to indicate that PP and PYY would be useful tumor markers for lung cancer in clinical management.
In vivo (Athens, Greece) 17(2):193-5. · 1.17 Impact Factor
