掲載種別：研究論文（学術雑誌）  

DOI： 10.70352/scrj.cr.25-0129

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Methionine restriction (MR) has been demonstrated to exhibit anti-tumor effects in various types of cancer, including pancreatic cancer (PC). However, the detailed mechanism induced by MR remains still unclear. This study aims to reveal the underlying mechanism of MR on PC by proteomic analysis. MATERIAL & METHODS: Human PC cell lines were cultured in both standard and MR media to evaluate the effect of MR. The differences in protein expression were evaluated through proteomic analysis. Ingenuity Pathway Analysis (IPA) was performed to identify proteins potentially associated with tumor growth in vitro. The proteins associated with the anti-tumor effect were validated using western blotting, real-time PCR, and ELISA. An experimental model involving subcutaneous PC mice was established for the assessment of the effectiveness of the MR diet and the expression of target proteins through immunohistochemical staining. RESULTS: Cell proliferation was suppressed in the MR media compared to the standard media. IPA analysis showed that STAT3 was decreased in the Apoptotic Pathway of Pancreatic Cancer Cell lines in the MR group. Western blotting showed MR decreased STAT3 expression. Real-time PCR showed that MR decreased JAK2 and STAT3 mRNA expression in Panc-1 and Mia-PaCa 2, but not in Capan-1. ELISA revealed that NF-kB expression was decreased in the MR group. In the in vivo study, the final estimated tumor volume in the MR group was significantly lower than the control group (p < 0.01). Immunostaining of resected specimens showed that STAT3 expression was suppressed in the MR group. CONCLUSION: MR suppressed the JAK2/STAT3 pathway and decreased NF-kB in some PC cell lines.

DOI： 10.1016/j.pan.2024.11.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

DOI： 10.1016/j.tice.2023.102125

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Methionine addiction, a fundamental and general hallmark of cancer, known as the Hoffman Effect, is due to altered use of methionine for increased and aberrant transmethylation reactions. However, the linkage of methionine addiction and malignancy of cancer cells is incompletely understood. An isogenic pair of methionine-addicted parental osteosarcoma cells and their rare methionine-independent revertant cells enabled us to compare them for malignancy, their epithelial-mesenchymal phenotype, and pattern of histone-H3 lysine-methylation. Methionine-independent revertant 143B osteosarcoma cells (143B-R) were selected from methionine-addicted parental cells (143B-P) by their chronic growth in low-methionine culture medium for 4 passages, which was depleted of methionine by recombinant methioninase (rMETase). Cell-migration capacity was compared with a wound-healing assay and invasion capability was compared with a transwell assay in 143B-P and 143B-R cells in vitro. Tumor growth and metastatic potential were compared after orthotopic cell-injection into the tibia bone of nude mice in vivo. Epithelial-mesenchymal phenotypic expression and the status of H3 lysine-methylation were determined with western immunoblotting. 143B-P cells had an IC₅₀ of 0.20 U/ml and 143B-R cells had an IC₅₀ of 0.68 U/ml for treatment with rMETase, demonstrating that 143B-R cells had regained the ability to grow in low methionine conditions. 143B-R cells had reduced cell migration and invasion capability in vitro, formed much smaller tumors than 143B-P cells and lost metastatic potential in vivo, indicating loss of malignancy in 143B-R cells. 143B-R cells showed gain of the epithelial marker, ZO-1 and loss of mesenchymal markers, vimentin, Snail, and Slug and, an increase of histone H3K9me3 and H3K27me3 methylation and a decrease of H3K4me3, H3K36me3, and H3K79me3 methylation, along with their loss of malignancy. These results suggest that shifting the balance in histone methylases might be a way to decrease the malignant potential of cells. The present results demonstrate the rationale to target methionine addiction for improved sarcoma therapy.

DOI： 10.3389/fonc.2022.1009548

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/cgp.20321

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pancreatic cancer is one of the most recalcitrant cancers, and more effective therapy is needed. Pre-clinical studies have shown that patient-derived orthotopic xenograft (PDOX) mouse models of pancreatic cancer are effectively treated with oral recombinant methioninase (o-rMETase). CASE REPORT: A 62-year-old woman diagnosed with stage IV pancreatic cancer was treated with the combination of 5-fluorouracil/leucovorin, irinotecan, and oxaliplatinum (FOLFIRINOX) every two weeks and o-rMETase twice a day as a supplement. The patient was also on a low-methionine diet. Disease progression was monitored by CA19-9 and computed tomography. The patient initially responded to FOLFIRINOX, shown by a great reduction in CA19-9 levels, with tumor shrinkage shown by computed tomography. The patient began taking o-rMETase and went on a low-methionine diet one year after diagnosis which she has maintained without side effects for 7 months. The patient's CA19-9 level and tumor size remain stable 19 months after diagnosis. The patient is alive and has maintained a high performance status. Historical data show that less than 5% of stage IV pancreatic-cancer patients on FOLFIRINOX have stable disease 1.5 years after diagnosis. CONCLUSION: The combination of o-rMETase and FOLFIRINOX may be synergistic in stage IV pancreatic cancer.

DOI： 10.21873/anticanres.15734

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Osteosarcoma is the most common bone sarcoma. Although surgery and chemotherapy are initially effective, the 5-year survival is approximately 60% to 80%, and has not improved over three decades. We have previously shown that methionine restriction (MR) induced by oral recombinant methioninase (o-rMETase), is effective against osteosarcoma in patient-derived orthotopic xenograft (PDOX) nude-mouse models. In the present report, the efficacy of the combination of oral o-rMETase and methotrexate (MTX) was examined in an osteosarcoma PDOX mouse model. MATERIALS AND METHODS: An osteosarcoma-PDOX model was previously established by implanting tumor fragments into the proximal tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups: control; o-rMETase alone; MTX alone; combination of o-rMETase and MTX. The mice were sacrificed after 4 weeks of treatment. RESULTS: The combination of o-rMETase and MTX showed significantly higher efficacy compared to the control group (p=0.04). The combination also showed significantly higher efficacy compared to MTX alone (p=0.04). No significant efficacy of o-rMETase alone or MTX alone compared to control was shown (p=0.21, 1.00, respectively). Only the combination of o-rMETase and MTX reduced the cancer-cell density in the osteosarcoma tumor. CONCLUSION: rMETase converted an osteosarcoma PDOX from MTX-resistant to MTX-sensitive and thereby shows future clinical potential.

DOI： 10.21873/anticanres.15531

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Attempts to selectively starve cancers in the clinic have been made at least since the time of Warburg beginning 100 years ago. Calorie-restriction or low-carbohydrate diets have had limited success with cancer patients. Methionine restriction is another strategy to selectively starve cancer cells, since cancers are addicted to methionine, unlike normal cells. Methionine addiction of cancer is termed the Hoffman effect. Numerous preclinical studies over the past half century have shown methionine restriction to be highly effective against all major cancer types and synergistic with chemotherapy. Low-methionine medical diets can be effective in lowering methionine and have shown some clinical promise, but they are not palatable and thereby not sustainable. However, selectively choosing among plant-based foods allows a variety of low-methionine diets that are sustainable. Our laboratory has developed a methioninase that can be administered orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer, including hormone-independent prostate cancer, and other recalcitrant cancers. The question is whether methionine restriction through a low-methionine diet, or even greater methionine restriction with methioninase in combination with a low-methionine diet, is ready for prime time in the clinic, especially in combination with other synergistic therapy. The question will hopefully be answered in the near future, especially for advanced cancer patients who have failed all standard therapy.

DOI： 10.21873/anticanres.15521

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research USA Inc.  

DOI： 10.21873/invivo.12875

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掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1117/12.2610557

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12605

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents. CASE REPORT: A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence. CONCLUSION: The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome.

DOI： 10.21873/anticanres.15438

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12602

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Methionine addiction is a fundamental and general hallmark of cancer cells, which require exogenous methionine, despite their ability to synthesize normal amounts of methionine from homocysteine. In contrast, methionine-independent normal cells do not require exogenous methionine in the presence of a methionine precursor. The methionine addiction of cancer cells is due to excess transmethylation reactions. We have previously shown that histone H3 lysine marks are over-methylated in cancer cells and the over-methylation is unstable when the cancer cells are restricted of methionine. In the present study, we show that methionine-addicted osteosarcoma cells are sensitive to both methotrexate (MTX) and recombinant methioninase (rMETase), but they affect histone H3 lysine-methylation in the opposite direction. Concentrations of MTX and rMETase, which inhibit osteosarcoma cells viability to 20%, had opposing effects on the status of histone methylation of H3K9me3 and H3K27me3. rMETase significantly decreased the amount of H3K9me3 and H3K27me3. In contrast, MTX significantly increased the amount of H3K9me and H3K27me3. The results suggest that increase or decrease in these methylated histone lysine marks is associated with proliferation arrest of methionine-addicted osteosarcoma.

DOI： 10.1016/j.bbrep.2021.101177

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/cgp.20292

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. MATERIALS AND METHODS: The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. RESULTS: Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. CONCLUSION: CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.

DOI： 10.21873/anticanres.15285

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/INVIVO.12534

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/INVIVO.12466

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment. MATERIALS AND METHODS: Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems. RESULTS: The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm. CONCLUSIONS: Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection.

DOI： 10.1016/j.jss.2021.02.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). METHODS: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks. RESULTS: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). CONCLUSION: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

DOI： 10.1007/s00280-021-04261-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic. MATERIALS AND METHODS: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined. RESULTS: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice. CONCLUSION: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.

DOI： 10.21873/anticanres.14943

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks. RESULTS: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively). CONCLUSION: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.

DOI： 10.21873/anticanres.14939

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/CGP.20246

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential. MATERIALS AND METHODS: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously. RESULTS: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×105, 1×105 and 5×104, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice. CONCLUSION: There is a tight linkage between methionine addiction and malignancy.

DOI： 10.21873/anticanres.14815

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DOI： 10.1101/2021.01.01.425040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer. METHODS: The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control). RESULTS: Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%). CONCLUSIONS: This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.

DOI： 10.1097/MPA.0000000000001709

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/INVIVO.12237

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DOI： 10.1101/2020.12.04.412437

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12150

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12149

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DOI： 10.21873/invivo.12151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The aim of the study was to determine if oral recombinant methioninase (o-rMETase) can sensitize an orthotopic bladder tumor in nude mice to low-dose cisplatinum (CDDP). MATERIALS AND METHODS: The green fluorescent protein (GFP)-expressing UM-UC-3-GFP bladder cancer was surgically orthotopically implanted (SOI) to the bladder in nude mice. The treatment was initiated when the primary tumor volume reached 100 mm3 Mice were assigned to 3 groups: G1: Saline vehicle (0.1 ml per mouse, oral, twice per day); G2: low-dose CDDP (0.5 mg/kg, intraperitoneal twice per week); G3: o-rMETase + low-dose CDDP (100 units per mouse, oral, twice per day + 0.5 mg/kg, intraperitoneal twice per week, respectively). Tumor volume and body weight were measured twice per week. The expression of Ki-67 was detected by immunohistochemistry to evaluate cell proliferation. RESULTS: The combination of o-rMETase and low-dose CDDP increased inhibition efficacy compared to low-dose CDDP monotherapy, on primary-tumor growth (p=0.032) and metastasis (p=0.002). CONCLUSION: The combination of o-rMETase with low-dose CDDP has future clinical potential for bladder cancer.

DOI： 10.21873/anticanres.14629

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12158

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ischemia reperfusion injury (IRI) during liver-metastasis resection for treatment of colon cancer may increase the risk of further metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been observed to exert a protective effect against IRI and IRI-induced metastasis of hepatocellular carcinoma. The present study aimed to investigate the effect of the PPARγ agonist pioglitazone on tumor metastasis and liver injury following IRI in a mouse model of colon cancer. Pioglitazone (30 mg/kg weight) was administered orally 1.5 h before and 2 h after the initiation of ischemia and was orally administrated daily to mice from day 0-21. SL4-cancer cells expressing red fluorescent protein (SL4-RFP) (1 × 106) were injected into the spleen. Fifteen minutes after injection, the hepatoduodenal ligament was clamped with a vessel clip, and released 5 min later. Liver, blood and tumor samples were taken from mice in order to determine if inflammation was induced by IRI. The effect of pioglitazone on liver metastasis was assessed. Furthermore, the effect of pioglitazone to control the inflammatory response during IRI progression was examined. Liver metastasis along with MMP-9 activation and the production of inflammatory cytokines were resistant to pioglitazone. Our results indicate that liver metastasis and associated inflammation in mice were resistant to pioglitazone.

DOI： 10.1038/s41598-020-75210-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.14547

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.12038

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DOI： 10.21873/invivo.12039

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.14489

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.11865

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.11866

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.14218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.14217

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.14221

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00280-019-03986-0

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/cgp.20165

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/invivo.11799

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.tice.2019.09.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In our process of standardizing laparoscopic right-sided anatomical hepatectomy, we found several advantages of the caudate lobe-first approach. We herein describe our standardized procedure of laparoscopic right posterior sectionectomy (Lap-RPS) using this approach. METHODS: Between January 2011 and January 2018, 31 patients underwent pure Lap-RPS in our hospital. The mean patient age was 68 years (range 47-85 years), and the number of male patients was more than that of female patients (64.5%). Of 31 patients, 20 had metastatic liver tumor, 7 had hepatocellular carcinoma, 3 had intrahepatic cholangiocellular carcinoma, and 1 had hemangioma. All 31 patients had Child-Pugh class A liver function. The surgical technique was recorded on video. Cumulative sum (CUSUM) analyses were applied to assess the learning curve. RESULTS: The mean operative time was 420 min (range 263-639 min), and the mean amount of blood loss was 304 g (range 10-900 g). No procedure was converted to open surgery. Postoperative bleeding, bile leakage, hepatic failure, and mortality did not occur. CUSUM analyses showed a decrease in the operative time and blood loss after using the caudate lobe-first approach. CONCLUSION: Our standardized procedure of Lap-RPS using the caudate lobe-first approach is not only feasible but also expected to provide an advantage for laparoscopic anatomical hepatectomy.

DOI： 10.1007/s00464-019-06877-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2019.08.051

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Laparoscopic hepatectomy for segment (S) 7 is classified as one of the most difficult procedures to perform.1 Here, we report a standardized method with the caudate lobe first approach2,3 which may benefit such difficult procedures. METHODS: A 76-year-old woman was diagnosed with multiple liver metastases after sigmoid colon cancer resection. Her liver function was normal. Abdominal CT showed multiple small tumors located in S3 (two), S7 (two), and S8 (two). RESULTS: After partial resection of S3, the right lobe was fully mobilized. The caudate lobe was first divided at the midline from the caudal side parallel to the ventral central line of the inferior vena cava, and the caudate process was detached from the posterior Glissonean pedicle. Then, the S7 Glissonean branch was exposed. After transecting it, the demarcation line was secured. The root of the right hepatic vein (RHV) was exposed by further transection of the caudate lobe. The superficial tissue was divided using ultrasonic shears, while the deeper tissue was divided using cavitron ultrasonic surgical aspirator. The main trunk of the RHV was continuously exposed from the caudodorsal side, transecting the S7 branches. Between the exposed main trunk of the RHV and the cutting line in the ventral liver surface, which had been marked on the left of the tumor in the dorsal part of S8, the liver parenchyma was divided, securing the surgical margin for all 4 tumors in S7 and S8. Specimens were placed into a retrieval bag and removed from the umbilicus incision. Operation time was 341 min, and estimated blood loss was 200 g. Metastatic adenocarcinoma was confirmed by postoperative pathological diagnosis. The postoperative course was uneventful. CONCLUSIONS: The caudate lobe first approach in laparoscopic hepatectomy for S7 is feasible and can benefit anatomical resection in such procedures.

DOI： 10.1007/s11605-018-4051-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.13492

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In our process of standardizing laparoscopic right hemihepatectomy (Lap-RH), we found several advantages of the laparoscopic caudate lobe first approach by using a unique laparoscopic caudodorsal view. METHODS: Between April 2012 and October 2017, 21 patients underwent pure Lap-RH at our hospital. The mean patient age was 62 years (range 36-75 years), and there were more male than female patients (66.7%). Of 21 patients, 11 had hepatocellular carcinoma, eight had metastatic tumor, and the other two had focal nodular hyperplasia and refractory liver abscess. All 21 patients had Child-Pugh class A liver function. The surgical technique was recorded on video. RESULTS: The mean operative time was 409 min (range 241-522 min), and the mean blood loss was 279 g (range 0-1,010 g). No procedure was converted to open surgery. With regard to postoperative complications, one patient had bile leakage from the stump of the main Glissonean branch and another patient had abscess formation in the subphrenic space. No postoperative bleeding, hepatic failure, and mortality occurred. CONCLUSIONS: Our standardized procedure of Lap-RH using the unique laparoscopic caudodorsal view is not only feasible but also confers a true advantage of the laparoscopic approach.

DOI： 10.1002/jhbp.563

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記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01117&link_issn=&doc_id=20170323300003&doc_link_id=10.5833%2Fjjgs.2015.0113&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2015.0113&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Gastroenterological Surgery  

DOI： 10.5833/jjgs.2015.0113

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：横浜市立大学医学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01499&link_issn=&doc_id=20161208380001&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1246%2F00000503%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1246%2F00000503%2F&type=%89%A1%95l%8Es%97%A7%91%E5%8Aw%81F%89%A1%95l%8Es%97%A7%91%E5%8Aw%8Aw%8Fp%8B%40%8A%D6%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80205_3.gif

記述言語：日本語   出版者・発行元：(一社)日本腹部救急医学会  

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03156&link_issn=&doc_id=20160714220034&doc_link_id=10.3919%2Fjjsa.77.1500&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.77.1500&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本腹部救急医学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Association of Yokohama City University  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00296&link_issn=&doc_id=20151027380026&doc_link_id=%2Fab8gtkrc%2F2015%2F004210%2F027%2F1246-1248%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2015%2F004210%2F027%2F1246-1248%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：日本外科系連合学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01066&link_issn=&doc_id=20150908090004&doc_link_id=10.4030%2Fjjcs.40.668&url=https%3A%2F%2Fdoi.org%2F10.4030%2Fjjcs.40.668&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：横浜市立大学医学会  

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