Publications (14)34.07 Total impact
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Article: [Highly advanced gastric cancer that responded to neoadjuvant combination chemotherapy with docetaxel/CDDP/S-1 (DCS)].
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ABSTRACT: A 60-year-old male was found to have advanced gastric cancer and multiple lymph node metastases. Since curative surgery was concluded to be unfeasible, we tried neoadjuvant chemotherapy with the aim of controlling the lymph node metastasis. S-1 (80 mg/m2) was administered orally for two weeks then followed by 2-week rest period. CDDP (60 mg/ m2) and docetaxel (40 mg/m2) were simultaneously administered on day 1. Two courses of treatment resulted in marked shrinkage of the primary lesion and a reduction in size of the lymph nodes. The results were evaluated as a clinical PR based on RECIST, and radical resection was considered possible. The patient experienced a grade 3 leukocytopenia and neutropenia as adverse events of the chemotherapy. Total gastrectomy, splenectomy, and D2 lymph node dissection were performed with curative intent, and the postoperative course was uneventful. Histological examination of the surgical specimens revealed almost complete disappearance of cancer cells in the primary lesion in the stomach and complete disappearance in the lymph nodes. Pathological efficacy was Grade 2. The patient experienced a grade 3 appetite loss, and the adjuvant chemotherapy (S-1 regimen) was discontinued. The patient died of peritoneal dissemination eight months after the operation. We concluded that DCS as neoadjuvant chemotherapy was a promising strategy for patients with highly advanced gastric cancer because of its rapid antitumor effect.Gan to kagaku ryoho. Cancer & chemotherapy 11/2010; 37(12):2470-2. -
Article: [A partial response to S-1 as second-line chemotherapy in a patient with unresectable pancreatic cancer].
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ABSTRACT: A male in his fifties presented with a primary complaint of abdominal distension and appetite loss. CT revealed a primary pancreatic tumor with massive ascites. The patient was treated with gemcitabine as the first-line chemotherapy. Gemcitabine (1,000 mg/m2) was intravenously administered 3 times (on days 1, 8, 15) every 4 weeks (days 1-28) as 1 course. CT revealed the size of the primary tumor to decrease and no ascites were observed. A new abdominal lesion appeared after 11 courses of gemcitabine. The time to progression was 11 months after the first-line chemotherapy. The patient was then treated with S-1 as second-line chemotherapy. S-1 (80 mg/m2) was orally administered daily for 4 weeks (days 1- 28) every 6 weeks. CT thereafter revealed a partial response. The patient experienced no adverse events. The time to progression was 6 months after starting the second-line chemotherapy. Gemcitabine is the standard regimen for unresectable pancreatic cancer. However, the benefits of second-line chemotherapy remain unclear. S-1 has been reported to show a considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. S-1 is therefore considered to be promising as second-line chemotherapy for unresectable pancreatic cancer, due to the fact that a considerable survival benefit has been observed for patients with unresectable pancreatic cancer.Gan to kagaku ryoho. Cancer & chemotherapy 11/2009; 36(12):2422-4. -
Article: Tumor initiating potential of side population cells in human gastric cancer.
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ABSTRACT: Side population (SP) cells are a small subpopulation of cells with enriched source of gastric tumor-initiating cells (TICs) with stem-like cell property that are characterized by high efflux ability of Hoechst 33342 dye, reflecting high expression of several subtypes of the ATP-binding cassette transporter family that is characteristic of stem cells. The present study is the first to discover and characterize SP cells within gastric cancer (GC) tumors. In this study, human GC cell lines (MKN45, KATOIII, MKN74, MKN28 and MKN1) were analyzed using flow cytometry for SP cell isolation, and all GC cell lines showed a distinct fraction of SP cells, ranging from 0.02+/-0.001 to 1.93+/-0.16%. Among these cell lines, MKN45 cultures possessed the highest percentage of SP cells. Using MKN45 cells, we demonstrated stem cell-like characteristics of SP cells of the cell lines as a possible subpopulation with enriched TICs, as indicated by ABC transporter gene expression (MDR1 and BCPR1), chemo-resistance and tumorigenicity in vivo. In addition, we report the first identification and isolation of SP cells from clinical GC tissues as well as human GC cell lines. These SP cells demonstrate higher tumorigenicity in vivo than does the overall cell population in the parent tissue. In conclusion, we demonstrate that solid tumor tissue such as human GC contains TICs, with the existence of heterogeneity and distinct hierarchy in malignancy, suggesting the future possibility of a novel therapeutic tool targeting TICs for overcoming this malignant disease.International Journal of Oncology 06/2009; 34(5):1201-7. · 2.40 Impact Factor -
Article: Intratumoral interferon-alpha gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation.
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ABSTRACT: One of the major challenges in the treatment of solid cancers by allogenic hematopoietic stem cell transfer (alloHSCT) is the specific enhancement of antitumor immunity. Interferon (IFN) is a cytokine with pleiotropic biological functions including an immunomoduration, and our preclinical studies have shown that an intratumoral IFN-alpha gene transfer induced strong local tumor control and systemic tumor-specific immunity. In the present study, we examined whether the IFN-alpha gene transfer could enhance recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. First, when a mouse IFN-alpha adenovirus vector (Ad-mIFN) was injected into subcutaneous xenografts of syngeneic renal and colon cancer cells, tumor growth was significantly suppressed in a dose-dependent manner. A significant tumor cell death and infiltration of immune cells was recognized in the Ad-mIFN-injected tumors, and the dendritic cells isolated from the tumors showed a strong Th1-oriented response. The antitumor effect of Ad-mIFN was then examined in a murine model of minor histocompatibility antigen-mismatched alloHSCT. The intratumoral IFN-alpha gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors which did not receive the vector injection. A cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to IFN-alpha. Graft-versus-host disease was not exacerbated serologically or clinically in the mice treated with IFN-alpha. This combination strategy deserves evaluation in future clinical trials for human solid cancers.Cancer Immunology and Immunotherapy 12/2008; 58(7):1007-21. · 3.70 Impact Factor -
Article: [A partial response to combined S-1 and CDDP chemotherapy enabling a curative resection in a patient with locally advanced duodenal cancer].
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ABSTRACT: A 60-year-old male presented with a primary complaint of back pain. CT revealed a primary duodenal tumor with bulky lymph node metastases. Gastrofiberscopy revealed a primary duodenal tumor located the second portion. The patient was treated with combined chemotherapy using S-1 and CDDP to prior to performing a surgical curative resection. S-1 (80 mg/m2) was orally administered for 3 weeks (day 1-21), and CDDP (60 mg/m2) was simultaneously administered on day 8 every 5 weeks. The chemotherapy was repeated for 2 cycles. The patient experienced no adverse event. CT revealed a partial response after chemotherapy. The patient underwent a curative pancreaticoduodenectomy. The pathological efficacy was Grade 2. Adjuvant chemotherapy was provided using S-1 regimen because of its pathological efficacy and the absence of severe adverse events. Six months after the operation, the patient was doing well and showed no signs of recurrence of the cancer. This S-1/CDDP combination chemotherapy was therefore considered to be suitable as neo-adjuvant chemotherapy because it permitted the patient to subsequently undergo a curative resection, and thereby achieving a survival benefit for locally advanced duodenal cancer.Gan to kagaku ryoho. Cancer & chemotherapy 12/2008; 35(12):2083-5. -
Article: Allogeneic MHC gene transfer enhances an effective antitumor immunity in the early period of autologous hematopoietic stem cell transplantation.
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ABSTRACT: In autologous hematopoietic stem cell transplantation (HSCT), lymphopenia-induced homeostatic proliferation of T cells is driven by the recognition of self-antigens, and there is an opportunity to skew the T-cell repertoire during the T-cell recovery by engaging tumor-associated antigens, leading to a break of tolerance against tumors. However, the homeostatic proliferation-driven antitumor responses seem to decline rapidly in association with tumor growth. We hypothesized that a tumor-specific immune response induced by an immune gene therapy could enhance and sustain homeostatic proliferation-induced antitumor immunity. The antitumor effect of allogeneic MHC (alloMHC) gene transfer was examined at the early phase of the immune reconstitution after syngeneic HSCT. Syngeneic HSCT showed significant tumor growth inhibition of syngeneic colon cancer cells within a period of 30 days; however, the tumor then resumed rapid growth and the survival of the mice was not prolonged. In contrast, when the alloMHC plasmid was intratumorally injected at the early phase after syngeneic HSCT, the established tumors were markedly regressed and the survival of recipient mice was prolonged without significant toxicities, whereas no survival advantage was recognized in recipient mice injected with a control plasmid. This tumor suppression was evident even in the other tumors that were not injected with the alloMHC plasmid. The antitumor response was characterized by the development of tumor-specific T cell- and natural killer cell-mediated cytotoxicities. The results suggest the efficacy and safety of integrating intratumoral alloMHC gene transfer with an autologous HSCT for the treatment of solid cancers.Clinical Cancer Research 01/2008; 13(24):7469-79. · 7.74 Impact Factor -
Article: [A case with a single liver metastasis from pancreatic cancer surviving for 29 months].
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ABSTRACT: We report a 62-year-old man with advanced pancreatic cancer who underwent pancreatoduodenectomy and was then found to have a single hepatic metastasis. Hepatic resection was performed after 19 months of systemic chemotherapy. The patient survived for 29 months after diagnosis of the hepatic metastasis without occurrence of further metastatic lesions. The patient was given a diagnosis of pancreatic head cancer and underwent pancreatoduodenectomy in September 2001. A single hepatic metastasis was found in July 2002. No local recurrence, lymph node metastasis, distant metastasis or peritoneal metastasis were noted on imaging studies. Chemotherapy with S-1 was performed. The hepatic metastasis remained single and there were no other metastatic lesions for 19 months. A metastasis was found in the right lung in May 2004. The patient died in December 2004 without local recurrence, lymph node metastasis or new hepatic metastasis.Gan to kagaku ryoho. Cancer & chemotherapy 11/2007; 34(10):1671-4. -
Article: A patient with gastric cancer and liver metastases successfully treated with combination chemotherapy including S-1.
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ABSTRACT: We report the case of a 62-year-old man with advanced gastric cancer and multiple liver metastases who was successfully treated with combined chemotherapy including S-1. The patient was clinically diagnosed with stage IV (T3 N2 H1 P0) disease and was initially treated with 100 mg/body per day S-1 administered orally for 21 days and 10 mg/body per day cisplatin (CDDP) infused on days 1-5, 8-12, and 15-19. This chemotherapy resulted in significant reduction of the liver and gastric tumors. After receiving additional CDDP/S-1 administration as an outpatient, the patient's liver masses disappeared as shown on abdominal computed tomography (CT). With the patient's desire and informed consent, he underwent curative surgery with total gastrectomy, D1+alpha lymph node dissection, and partial resection of liver S4. After discharge without any surgical complication, CT revealed regrowth of the S4 liver mass, and combined docetaxel and CDDP was selected as second-line chemotherapy with local radiation therapy against the hepatic metastasis. Additionally, a third regimen with irinotecan and S-1 was given. At 2 years 7 months after the initial treatment, no sign of cancer (including liver metastasis and peritoneal dissemination) has been identified by radiological follow-up examinations.International Journal of Clinical Oncology 09/2007; 12(4):295-9. · 1.41 Impact Factor -
Article: Local interferon-alpha gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster.
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ABSTRACT: The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN-alpha did not show cross-species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN-alpha effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN-alpha augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN-alpha gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN-alpha adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM-1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and natural killer cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM-1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN-alpha gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity.Cancer Science 04/2007; 98(3):455-63. · 3.33 Impact Factor -
Article: Allogeneic MHC gene transfer enhances antitumor activity of allogeneic hematopoietic stem cell transplantation without exacerbating graft-versus-host disease.
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ABSTRACT: Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen-mismatched alloHSCT (DBA/2-->BALB/c: H-2(d)) recipients, alloMHC gene (H-2K(b)) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2K(b) gene transfer provides only a limited antitumor effect after syngeneic (BALB/c-->BALB/c) HSCT. By contrast, the H-2K(b) gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2K(b) gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.Clinical Cancer Research 04/2006; 12(7 Pt 1):2208-15. · 7.74 Impact Factor -
Article: Intraperitoneal injection of adenovirus expressing antisense K-ras RNA suppresses peritoneal dissemination of hamster syngeneic pancreatic cancer without systemic toxicity.
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ABSTRACT: We examined the antitumor effect and safety of the adenovirus-mediated expression of antisense K-ras RNA in two peritoneal dissemination models of pancreatic cancer. First, we found that the infection of an adenovirus vector expressing antisense human K-ras RNA (AxCA-AS) induced significant apoptosis in vitro in human pancreatic cancer cells with K-ras mutation. Second, the intraperitoneal (ip) injection of AxCA-AS effectively suppressed the growth of human pancreatic cancer cells in the peritoneal cavity of nude mice. Third, in the hamster syngeneic peritoneal dissemination model, the ip injection of an adenovirus expressing antisense hamster K-ras RNA significantly suppressed the peritoneal growth of hamster pancreatic cancer cells, and no significant systemic toxicity was observed in the treated hamsters. This study suggests a feasibility of the development of a therapeutic strategy against pancreatic cancer based on the adenovirus-mediated transduction of an antisense K-ras construct.Cancer Letters 02/2005; 218(1):53-62. · 4.24 Impact Factor -
Article: [A case of advanced gallbladder cancer with biliary tract stenosis which responded to TS-1 chemotherapy].
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ABSTRACT: TS-1 is reported to be beneficial for advanced gastric cancer, but there is no report on its use for advanced gallbladder cancer. The present patient was a 64-year-old woman with advanced gallbladder cancer with severe biliary tract stenosis. The primary tumor was located in the neck of the gallbladder and peripancreatic lymph node metastasis was detected. TS-1 100 mg/day was administered orally for 21 days and CDDP 30 mg/day on days 1, 8 by drip infusion. Grade 4 neutropenia was observed in the first cycle, and TS-1 alone was used for further treatment. After 2 courses, primary tumor showed PR and lymph node metastasis had disappeared. Biliary stenosis was remarkably improved. We conclude that TS-1 might be beneficial in the treatment of advanced gallbladder cancer.Gan to kagaku ryoho. Cancer & chemotherapy 08/2003; 30(7):1013-6. -
Article: Effects of phalloidin on the biliary excretion of cholephilic compounds in rats.
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ABSTRACT: Phalloidin is known to cause cholestasis by preventing microfilament depolymerization. In addition, phalloidin is reported to inhibit the vesicular targeting of canalicular transporters. The aim of the present study was to examine the effect of phalloidin on the biliary excretion of substrates typical for various canalicular transporters in rats. Phalloidin decreased the biliary excretion of tracer amounts of taurocholate, leukotriene C(4), pravastatin, and vinblastine. Increases in bile flow and biliary bile acid excretion caused by taurocholate infusion were completely inhibited by phalloidin. These data indicate that, in addition to multidrug resistance protein 2 and P glycoprotein, the vesicular targeting of the bile salt export pump, a major canalicular bile acid transporter, is also impaired by phalloidin. The decrease of biliary excretion of glutathione may also relate to the increase in the bile acid independent canalicular bile flow in phalloidin-treated rats.Pharmacology 10/2002; 66(1):31-5. · 1.79 Impact Factor -
Article: Role of the MTT chemosensitivity test in the prognosis of gastric cancer patients after postoperative adjuvant chemotherapy.
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ABSTRACT: The clinical usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) chemosensitivity test (MTT assay; MTTA) in the selection of anticancer drugs against advanced gastric cancer (AGC) was evaluated. MTTA is widely used to predict patient responses to particular drugs, allowing for the selection of appropriate chemotherapeutic drugs and the avoidance of ineffective chemotherapeutic drugs, thereby improving patient survival. Since 1989, we have accumulated MTTA efficacy data from AGC patients. In this study, the present clinical roles of MTTA and the data from 202 patients with stage III or IV gastric cancer analyzed for survival outcome following surgery, with or without postoperative chemotherapy, evaluated by MTTA, are discussed. The patients were divided into 3 groups; an adapted group found to be sensitive to chemotherapy by MTTA, a non-adapted group found to be insensitive to chemotherapy by MTTA and a group that received no chemotherapy. For stage III gastric cancer patients, the adapted group had a statistically better survival rate compared to the other groups, while for stage IV patients, there was no difference in survival rate between any of the groups. However, further classification of stage IV patients as to the presence or absence of peritoneal dissemination (P) showed that the adapted group with P showed better prognoses than the other groups with P. The analysis of data collected since 2000 revealed that the 11 patients in the taxane-adapted group, who received chemotherapeutic regimens that included taxanes and were found to be sensitive to taxanes by MTTA, demonstrated better survival than the taxane non-adapted group (n=11) (p=0.045). In conclusion, MTTA results predicted patient prognoses, based on the selection of appropriate chemotherapy.Anticancer research 26(2B):1433-7. · 1.73 Impact Factor
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2005–2008
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National Cancer Center
Tokyo, Tokyo-to, Japan
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