40 results on '"Takuhei Yokoyama"'
Search Results
2. Supplementary method from LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake
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Tetsuji Naka, Tadashi Kimura, Eiichi Morii, Kiyoshi Yoshino, Yutaka Ueda, Hiroshi Takemori, Minoru Fujimoto, Tsuyoshi Takahashi, Takuhei Yokoyama, Shinya Matsuzaki, Akiko Morimoto, Satoshi Nojima, Satoshi Nakagawa, Yusuke Takahashi, Takayuki Enomoto, Satoshi Serada, and Kosuke Hiramatsu
- Abstract
This article shows how to product anti-LSR antibody
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- 2023
3. Supplementary Table S4 from LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake
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Tetsuji Naka, Tadashi Kimura, Eiichi Morii, Kiyoshi Yoshino, Yutaka Ueda, Hiroshi Takemori, Minoru Fujimoto, Tsuyoshi Takahashi, Takuhei Yokoyama, Shinya Matsuzaki, Akiko Morimoto, Satoshi Nojima, Satoshi Nakagawa, Yusuke Takahashi, Takayuki Enomoto, Satoshi Serada, and Kosuke Hiramatsu
- Abstract
This table shows no toxicity of anti-hLSR mAb in mice
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- 2023
4. Supplementary Table S2 and S3 from LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake
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Tetsuji Naka, Tadashi Kimura, Eiichi Morii, Kiyoshi Yoshino, Yutaka Ueda, Hiroshi Takemori, Minoru Fujimoto, Tsuyoshi Takahashi, Takuhei Yokoyama, Shinya Matsuzaki, Akiko Morimoto, Satoshi Nojima, Satoshi Nakagawa, Yusuke Takahashi, Takayuki Enomoto, Satoshi Serada, and Kosuke Hiramatsu
- Abstract
These tables shows LSR immunostaining distribution of patients with ovarian serous carcinoma (Table S2) and clear cell carcinoma (Table S3)
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- 2023
5. Data from LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake
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Tetsuji Naka, Tadashi Kimura, Eiichi Morii, Kiyoshi Yoshino, Yutaka Ueda, Hiroshi Takemori, Minoru Fujimoto, Tsuyoshi Takahashi, Takuhei Yokoyama, Shinya Matsuzaki, Akiko Morimoto, Satoshi Nojima, Satoshi Nakagawa, Yusuke Takahashi, Takayuki Enomoto, Satoshi Serada, and Kosuke Hiramatsu
- Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR+ EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro, and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.Significance: These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. Cancer Res; 78(2); 516–27. ©2017 AACR.
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- 2023
6. Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma
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Shiori Yanai, Erin A. Blake, Masayuki Yoshida, Satoshi Takeuchi, Yoshiaki Yuba, Hiroko Machida, Yutaka Ueda, Hiroshi Kajiwara, Keita Iwasaki, Merieme Klobocista, Masako Shida, Todd B. Sheridan, Terry K. Morgan, Masato Nishimura, Marian S. Johnson, Koji Matsuo, Shinya Satoh, Munetaka Takekuma, Joseph L. Kelley, Esther Elishaev, Tadayoshi Nagano, Abby M. Richmond, Takuya Moriya, Kiyoshi Yoshino, Tanja Pejovic, Malcolm S. Ross, Lynda D. Roman, Takeshi Sasaki, Masanori Yasuda, Mayu Yunokawa, Ardeshir Hakam, Takahito Miyake, Kosei Hasegawa, Tadao Takano, Paulette Mhawech-Fauceglia, Kohei Omatsu, Hiroshi Yoshida, Sosuke Adachi, Stephen H. Bush, Takayuki Enomoto, Miriam D. Post, Tomoyuki Fukagawa, Yuji Ikeda, Takuhei Yokoyama, Yutaka Takazawa, Tsukasa Baba, Mian M.K. Shahzad, Frederick R. Ueland, Dwight D. Im, and Rouzan G. Karabakhtsian
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0301 basic medicine ,medicine.medical_specialty ,Hysterectomy ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Internal medicine ,medicine ,Carcinoma ,Humans ,Neoplasm Invasiveness ,Progression-free survival ,Survival rate ,Lymphatic Vessels ,Retrospective Studies ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Primary tumor ,Progression-Free Survival ,Lymphovascular ,Survival Rate ,030104 developmental biology ,Oncology ,Chemotherapy, Adjuvant ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Disease Progression ,Blood Vessels ,Female ,Radiotherapy, Adjuvant ,Surgery ,Histopathology ,Sarcoma ,business - Abstract
OBJECTIVE. The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS. This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I–IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS. Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36–2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39–2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION. In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.
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- 2018
7. Significance of venous thromboembolism in women with uterine carcinosarcoma
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Joseph L. Kelley, Sosuke Adachi, Mian M.K. Shahzad, Tadayoshi Nagano, Marian S. Johnson, Shiori Yanai, Erin A. Blake, Hiroko Machida, Koji Matsuo, Munetaka Takekuma, Tanja Pejovic, Malcolm S. Ross, Tadao Takano, Yutaka Ueda, Lynda D. Roman, Shinya Satoh, Satoshi Takeuchi, Keita Iwasaki, Masako Shida, Takahito Miyake, Kosei Hasegawa, Frederick R. Ueland, Masato Nishimura, Stephen H. Bush, Dwight D. Im, Takuhei Yokoyama, Merieme Klobocista, Mayu Yunokawa, Yuji Ikeda, Tsukasa Baba, and Kohei Omatsu
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medicine.medical_specialty ,Neoplasm, Residual ,Multivariate analysis ,Population ,Kaplan-Meier Estimate ,Gastroenterology ,Article ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Carcinosarcoma ,Risk Factors ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,030212 general & internal medicine ,Neoplasm Metastasis ,education ,Aged ,Retrospective Studies ,education.field_of_study ,business.industry ,Surrogate endpoint ,Incidence (epidemiology) ,Hazard ratio ,Obstetrics and Gynecology ,Retrospective cohort study ,Venous Thromboembolism ,Middle Aged ,medicine.disease ,Tumor Burden ,Pulmonary embolism ,Oncology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,business - Abstract
OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P = 0.012), non-Asian race (HR 6.28, P< 0.001), large body habitus (HR per kg/m(2) 1.04, P = 0.014), residual disease at surgery (HR 3.04, P = 0.003), tumor size ≥5 cm (HR2.73, P = 0.003), and stage IV disease (HR2.12, P = 0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P< 0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P = 0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46,95%CI 1.05–2.04, P = 0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.
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- 2018
8. LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake
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Kosuke Hiramatsu, Tetsuji Naka, Takayuki Enomoto, Shinya Matsuzaki, Akiko Morimoto, Satoshi Nojima, Satoshi Nakagawa, Tadashi Kimura, Eiichi Morii, Minoru Fujimoto, Kiyoshi Yoshino, Takuhei Yokoyama, Hiroshi Takemori, Yutaka Ueda, Tsuyoshi Takahashi, Yusuke Takahashi, and Satoshi Serada
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Male ,Proteomics ,0301 basic medicine ,Cancer Research ,endocrine system diseases ,Apoptosis ,Carcinoma, Ovarian Epithelial ,Mice ,0302 clinical medicine ,Tumor Cells, Cultured ,Tissue Distribution ,Neoplasms, Glandular and Epithelial ,Ovarian Neoplasms ,Mice, Inbred BALB C ,biology ,Antibodies, Monoclonal ,Middle Aged ,Prognosis ,Lipids ,female genital diseases and pregnancy complications ,Tumor antigen ,Survival Rate ,Oncology ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,Antibody ,Adult ,medicine.drug_class ,Mice, Nude ,Monoclonal antibody ,03 medical and health sciences ,Antigen ,In vivo ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Aged ,Cell Proliferation ,Receptors, Lipoprotein ,Cell growth ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Mice, Inbred C57BL ,030104 developmental biology ,Case-Control Studies ,Immunology ,Cancer research ,biology.protein ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR+ EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro, and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment. Significance: These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. Cancer Res; 78(2); 516–27. ©2017 AACR.
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- 2018
9. Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma
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Keita Iwasaki, Tanja Pejovic, Mian M.K. Shahzad, Yutaka Ueda, Lynda D. Roman, Takuhei Yokoyama, Sosuke Adachi, Shinya Satoh, Joseph L. Kelley, Hiroko Machida, Satoshi Takeuchi, Tadayoshi Nagano, Frederick R. Ueland, Stephen H. Bush, Dwight D. Im, Mayu Yunokawa, Shiori Yanai, Malcolm S. Ross, Erin A. Blake, Marian S. Johnson, Koji Matsuo, Tadao Takano, Takahito Miyake, Merieme Klobocista, Kosei Hasegawa, Masako Shida, Kohei Omatsu, Tsukasa Baba, Yuji Ikeda, Masato Nishimura, and Munetaka Takekuma
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Bridged-Ring Compounds ,Oncology ,medicine.medical_specialty ,Organoplatinum Compounds ,medicine.medical_treatment ,Salvage therapy ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Japan ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Retrospective Studies ,Salvage Therapy ,Univariate analysis ,Chemotherapy ,030219 obstetrics & reproductive medicine ,Taxane ,business.industry ,Obstetrics and Gynecology ,Retrospective cohort study ,Middle Aged ,Chemotherapy regimen ,United States ,Regimen ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cohort ,Female ,Taxoids ,Neoplasm Recurrence, Local ,business - Abstract
OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P < 0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P = 0.02). When stratified by disease-free interval, women with a disease-free interval ≥6 months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P = 0.002); conversely, in women with a disease-free interval
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- 2017
10. Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma
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Stephen H. Bush, Takuhei Yokoyama, Masato Nishimura, Satoshi Takeuchi, Tanja Pejovic, Frederick R. Ueland, Dwight D. Im, Kohei Omatsu, Malcolm S. Ross, Lynda D. Roman, Masako Shida, Joseph L. Kelley, Tsukasa Baba, Merieme Klobocista, Yutaka Ueda, Tadao Takano, Munetaka Takekuma, Shiori Yanai, Erin A. Blake, Hiroko Machida, Shinya Satoh, Tadayoshi Nagano, Yuji Ikeda, Marian S. Johnson, Koji Matsuo, Keita Iwasaki, Sosuke Adachi, Mayu Yunokawa, Kosei Hasegawa, Takahito Miyake, and Mian M.K. Shahzad
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Brachytherapy ,Kaplan-Meier Estimate ,Hysterectomy ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,medicine ,Adjuvant therapy ,Humans ,030212 general & internal medicine ,Neoplasm Staging ,Proportional Hazards Models ,Retrospective Studies ,Chemotherapy ,business.industry ,Obstetrics and Gynecology ,Retrospective cohort study ,Chemoradiotherapy, Adjuvant ,Middle Aged ,medicine.disease ,Confidence interval ,Radiation therapy ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,Radiotherapy, Adjuvant ,Sarcoma ,Neoplasm Recurrence, Local ,business - Abstract
BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25–0.83, P = 0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27–0.62, P < 0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13–1.58, P = 0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P < 0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02–0.90; P = 0.013) but not in none/single factor (P = 0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.
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- 2017
11. Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP
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Jung-Min Lee, Ethan Brill, Elise C. Kohn, and Takuhei Yokoyama
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0301 basic medicine ,Cancer Research ,Cell ,apoptosis ,synergy ,Articles ,Cell cycle ,Biology ,Molecular medicine ,03 medical and health sciences ,ovarian cancer ,PARP inhibitor ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Annexin ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Cytotoxic T cell ,Viability assay ,BH3-mimetic - Abstract
The aim of our study was to evaluate possible synergistic cytotoxic effects of the combination treatment with the BH3-mimetic ABT-263 and the PARP inhibitor BMN 673 in high-grade serous ovarian cancer (HGSOC) cells using clinically achievable concentrations of each drug. In vitro cytotoxic effects of ABT-263 and BMN 673 were assessed by XTT assay in three HGSOC cell lines: OVCAR3, OVCAR8, and OV90 cells. Combination index values and synergy/antagonism volumes were used to determine synergy. The drug effects on DNA damage accumulation, cell cycle progression, apoptosis induction, and expression levels of Bcl-2 family proteins were examined to dissect molecular mechanisms. The combination treatment synergistically decreased cell viability in a concentration- and time-dependent manner in all cell lines; combination index values were 100 after 72 h of treatment. Clinically achievable concentrations of ABT-263 2 µM and BMN 673 25 nM were used to investigate mechanisms. No increase in γ-H2AX foci formation was observed with addition of ABT-263 to BMN 673 treatment. The combination treatment increased the sub-G1 and Annexin V-positive cell populations after 48 h compared with the control and each monotherapy. It also induced greater caspase-3/7 activity and PARP cleavage. ABT-263 alone and in combination with BMN 673 induced expression levels of Bim, a pro-apoptotic protein. In conclusion, the ABT-263 and BMN 673 combination resulted in synergistic cytotoxic effects against HGSOC cells through greater induction of apoptosis. This may be a novel therapeutic strategy for HGSOC.
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- 2017
12. Tumor characteristics and outcome of uterine carcinosarcoma in women aged ≥80 years
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Sosuke Adachi, Masato Nishimura, Takahito Miyake, Kosei Hasegawa, Malcolm S. Ross, Tanja Pejovic, Mian M.K. Shahzad, Shiori Yanai, Erin A. Blake, Lynda D. Roman, Joseph L. Kelley, Yutaka Ueda, Tadao Takano, Marian S. Johnson, Merieme Klobocista, Koji Matsuo, Munetaka Takekuma, Mayu Yunokawa, Stephen H. Bush, Masako Shida, Takuhei Yokoyama, Kohei Omatsu, Keita Iwasaki, Tadayoshi Nagano, Hiroko Machida, Shinya Satoh, Satoshi Takeuchi, Yuji Ikeda, Tsukasa Baba, Frederick R. Ueland, and Dwight D. Im
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0301 basic medicine ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Hysterectomy ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Secondary analysis ,Internal medicine ,Adjuvant therapy ,Medicine ,Humans ,Neoplasm Invasiveness ,Uterine carcinosarcoma ,Stage (cooking) ,Aged ,Retrospective Studies ,Simple hysterectomy ,Aged, 80 and over ,business.industry ,Retrospective cohort study ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Survival Rate ,030104 developmental biology ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Lymph Node Excision ,Surgery ,Lymphadenectomy ,Female ,Radiotherapy, Adjuvant ,business ,Follow-Up Studies - Abstract
OBJECTIVE: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged ≥80 years. METHODS: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I–IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged ≥80 (n = 82 [9.1%]), aged 60–79, (n = 526 [58.1%]), and aged < 60 (n = 298 [32.9%]). RESULTS: Women in the aged ≥80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged ≥80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged ≥80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged ≥80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22–0.89, P = 0.021). With chemotherapy treatment, women in the aged ≥80 group had PFS similar to those in the aged 60–79 group (HR 0.97, 95%CI 0.51–1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged ≥80 group had significantly decreased PFS compared to the aged 60–79 group (HR 1.62, 95%CI 1.09–2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. CONCLUSION: Nearly 10% of women with UCS are aged ≥80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.
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- 2018
13. Proposal for a Risk-Based Categorization of Uterine Carcinosarcoma
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Satoshi Takeuchi, Joseph L. Kelley, Takeshi Sasaki, Todd B. Sheridan, Kiyoshi Yoshino, Sosuke Adachi, Mayu Yunokawa, Yuji Ikeda, Takayuki Enomoto, Munetaka Takekuma, Ardeshir Hakam, Merieme Klobocista, Takuya Moriya, Stephen H. Bush, Terry K. Morgan, Hiroshi Kajiwara, Tanja Pejovic, Yutaka Takazawa, Abby M. Richmond, Keita Iwasaki, Takuhei Yokoyama, Frederick R. Ueland, Yoshiaki Yuba, Lynda D. Roman, Yutaka Ueda, Dwight D. Im, Masanori Yasuda, Miriam D. Post, Hiroko Machida, Malcolm S. Ross, Tomoyuki Fukagawa, Masato Nishimura, Shinya Satoh, Takahito Miyake, Tsukasa Baba, Kohei Omatsu, Kosei Hasegawa, Esther Elishaev, Tadao Takano, Paulette Mhawech-Fauceglia, Marian S. Johnson, Koji Matsuo, Tadayoshi Nagano, Hiroshi Yoshida, Rouzan G. Karabakhtsian, Mian M.K. Shahzad, Shiori Yanai, Erin A. Blake, Masayuki Yoshida, and Masako Shida
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Pilot Projects ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Surgical oncology ,Risk Factors ,Internal medicine ,medicine ,Carcinoma ,Humans ,Neoplasm Invasiveness ,Survival rate ,Lymph node ,Dominance (genetics) ,Retrospective Studies ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,Uterine Neoplasms ,Etiology ,Surgery ,Female ,Sarcoma ,business ,Follow-Up Studies - Abstract
PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.
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- 2018
14. Characterizing sarcoma dominance pattern in uterine carcinosarcoma: Homologous versus heterologous element
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Malcolm S. Ross, Kiyoshi Yoshino, Keita Iwasaki, Takahito Miyake, Tadao Takano, Esther Elishaev, Sosuke Adachi, Yoshiaki Yuba, Tomoyuki Fukagawa, Takuya Moriya, Kosei Hasegawa, Hiroshi Kajiwara, Takuhei Yokoyama, Terry K. Morgan, Yutaka Takazawa, Paulette Mhawech-Fauceglia, Masanori Yasuda, Joseph L. Kelley, Takeshi Sasaki, Abby M. Richmond, Tadayoshi Nagano, Shiori Yanai, Masato Nishimura, Frederick R. Ueland, Tsukasa Baba, Erin A. Blake, Masayuki Yoshida, Satoshi Takeuchi, Dwight D. Im, Tanja Pejovic, Mayu Yunokawa, Kohei Omatsu, Miriam D. Post, Hiroko Machida, Ardeshir Hakam, Todd B. Sheridan, Shinya Satoh, Yuji Ikeda, Lynda D. Roman, Stephen H. Bush, Yutaka Ueda, Munetaka Takekuma, Hiroshi Yoshida, Masako Shida, Mian M.K. Shahzad, Rouzan G. Karabakhtsian, Merieme Klobocista, Marian S. Johnson, and Koji Matsuo
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Heterologous ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Internal medicine ,Carcinoma ,Homologous chromosome ,Medicine ,Humans ,Survival rate ,Dominance (genetics) ,Retrospective Studies ,Chemotherapy ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Cystadenocarcinoma, Serous ,Endometrial Neoplasms ,Radiation therapy ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Surgery ,Female ,Sarcoma ,business ,Adenocarcinoma, Clear Cell ,Follow-Up Studies - Abstract
OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns In uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35–1.69, and hetero/dominance 1.47–1.64) and CSS (adjusted-HR ranges: 1.52–1.84 and 1.66–1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.
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- 2018
15. Clinical utility of CA-125 in the management of uterine carcinosarcoma
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Munetaka Takekuma, Marian S. Johnson, Koji Matsuo, Keita Iwasaki, Tadayoshi Nagano, Frederick R. Ueland, Dwight D. Im, Satoshi Takeuchi, Joseph L. Kelley, Tsukasa Baba, Shinya Satoh, Mayu Yunokawa, Merieme Klobocista, Masato Nishimura, Sosuke Adachi, Stephen H. Bush, Malcolm S. Ross, Hiroko Machida, Yutaka Ueda, Takuhei Yokoyama, Yuji Ikeda, Kohei Omatsu, Masako Shida, Tadao Takano, Shiori Yanai, Erin A. Blake, Tanja Pejovic, Lynda D. Roman, Mian M.K. Shahzad, Takahito Miyake, and Kosei Hasegawa
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Ca 125 antigen ,Black People ,White People ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Carcinosarcoma ,Correspondence ,Humans ,Medicine ,Uterine carcinosarcoma ,Uterine Neoplasm ,Aged ,Retrospective Studies ,business.industry ,Racial Groups ,Age Factors ,Obstetrics and Gynecology ,General Medicine ,Middle Aged ,medicine.disease ,National Cancer Institute (U.S.) ,United States ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,business ,SEER Program - Abstract
Uterine carcinosarcoma (UCS) is a rare type of high-grade endometrial cancer (EC) that has been understudied with population-based statistics due to its rarity. This study examined temporal trends in the proportion of UCS among women with EC.This is a retrospective observational study examining The Surveillance, Epidemiology, and End Results program between 1973-2013. Primary EC cases were eligible for analysis, and a time-specific proportion of UCS was examined during the study period.UCS was seen in 11,000 (4.7%) women among 235,849 primary EC cases. Mean age at UCS diagnosis increased from 65.9 to 71.7 years between 1973-1989 and then decreased from 71.7 to 67.0 years between 1989-2013 (both, p0.001). Proportion of Black women significantly increased during the study period (11.9%-20.0%, p0.001), whereas the proportion of White women decreased from 86.0% to 60.5% between 1987-2013 (p0.001). There was a significant increase in the proportion of UCS among primary EC from 1.7% to 5.6% between 1973-2013 (p0.001). Among type II ECs (n=76,118), the proportion of UCS also increased significantly from 6.0% to 17.5% between 1973-2013 (p0.001). An increasing proportion of UCS was seen in both young and older women but the magnitude of interval increase was larger in the older age group between 1973-2013 (60 years, from 1.3% to 3.3%. p0.001; and ≥60 years, from 2.6% to 7.0%, p0.001).Our study demonstrated that the proportion of UCS has significantly increased among EC, accounting for more than 5% in recent years.
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- 2018
16. Survival outcome of stage I ovarian clear cell carcinoma with lympho-vascular space invasion
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Ikuo Konishi, Anil K. Sood, Kosuke Hiramatsu, Todd B. Sheridan, Kiyoshi Yoshino, Takayuki Enomoto, Ryusuke Murakami, Christina Fotopoulou, Sosuke Adachi, Koji Matsuo, Kosei Hasegawa, Lynda D. Roman, Keiichi Fujiwara, Masato Nishimura, Noriomi Matsumura, Takuhei Yokoyama, and Yuji Ikeda
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Carcinoma, Ovarian Epithelial ,Risk Factors ,Internal medicine ,medicine ,Humans ,Neoplasms, Glandular and Epithelial ,Stage (cooking) ,Survival analysis ,Lymphatic Vessels ,Neoplasm Staging ,Ovarian Neoplasms ,Univariate analysis ,business.industry ,Hazard ratio ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Survival Analysis ,Regimen ,Treatment Outcome ,Lymphatic Metastasis ,Clear cell carcinoma ,Lymph Node Excision ,Female ,Lymphadenectomy ,Lymph Nodes ,Ovarian cancer ,business ,Adenocarcinoma, Clear Cell - Abstract
Background The clinical impact of lympho-vascular space invasion (LVSI) in early-stage ovarian clear cell carcinoma (OCCC) is not well understood. Given the distinct tumor biology and survival patterns of OCCC, the significance of LVSI on survival outcome and treatment response was examined in OCCC. Methods A multicenter study was conducted to examine stage IA–IC3 OCCC cases that underwent primary surgical staging including lymphadenectomy. LVSI status was determined from archived histopathology slides, correlated with clinico-pathological results, chemotherapy patterns, and survival outcomes. Results LVSI was observed in 47 (20.3%) among 232 cases. In univariate analysis, LVSI was associated with older age ( p =0.042), large tumor size ( p =0.048), and stage IC ( p =0.035). In survival analysis, LVSI was associated with decreased disease-free survival (DFS, 5-year rate, 70.6% versus 92.1%, p =0.0004) and overall survival (OS, 78.8% versus 93.3%, p =0.008) on univariate analysis. After controlling for age, tumor size, stage, and chemotherapy use, LVSI remained an independent prognostic factor for decreased survival outcomes (DFS, hazard ratio [HR] 4.35, 95% confidence interval [CI] 1.73–10.9, p =0.002; and OS, HR 4.73, 95%CI 1.60–14.0, p =0.015). Among 210 cases who received postoperative chemotherapy, while regimen type did not impact survival outcome regardless of LVSI status (DFS, p =0.63), the number of administered cycles showed a survival benefit towards ≥6cycles for patients with LVSI-positive tumors (DFS, p =0.009; and OS, p =0.016). Conclusion LVSI is an important marker to predict survival outcome of stage I OCCC. Regardless of chemotherapy type, patients with stage I OCCC showing LVSI may benefit from receiving postoperative chemotherapy.
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- 2015
17. Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery
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Satoshi Takeuchi, Sosuke Adachi, Kohei Omatsu, Hiroko Machida, Masato Nishimura, Marian S. Johnson, Munetaka Takekuma, Masako Shida, Koji Matsuo, Malcolm S. Ross, Frederick R. Ueland, Dwight D. Im, Joseph L. Kelley, Tadao Takano, Mayu Yunokawa, Tsukasa Baba, Shinya Satoh, Takuhei Yokoyama, Stephen H. Bush, Takahito Miyake, Keita Iwasaki, Shiori Yanai, Kosei Hasegawa, Erin A. Blake, Tanja Pejovic, Lynda D. Roman, Yuji Ikeda, Tadayoshi Nagano, Yutaka Ueda, Mian M.K. Shahzad, and Merieme Klobocista
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Oncology ,medicine.medical_specialty ,Paclitaxel ,medicine.medical_treatment ,Hysterectomy ,Article ,Disease-Free Survival ,Carboplatin ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinosarcoma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Neoadjuvant therapy ,Neoplasm Staging ,Retrospective Studies ,Chemotherapy ,business.industry ,Case-control study ,Retrospective cohort study ,General Medicine ,Middle Aged ,Neoadjuvant Therapy ,Surgery ,Regimen ,chemistry ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Case-Control Studies ,Uterine Neoplasms ,Female ,business ,Cohort study - Abstract
Background and Objectives To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. Methods This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. Results The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. Conclusion Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.
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- 2017
18. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases
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Ethan, Brill, Takuhei, Yokoyama, Jayakumar, Nair, Minshu, Yu, Yeong-Ran, Ahn, and Jung-Min, Lee
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PARP inhibitor ,prexasertib ,cell cycle checkpoint kinase inhibitor ,LY2606368 ,olaparib ,Research Paper - Abstract
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations. Our findings showed combination treatment synergistically decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than the control and/or monotherapies (p
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- 2017
19. Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma
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Malcolm S. Ross, Takuhei Yokoyama, Satoshi Takeuchi, Tadao Takano, Merieme Klobocista, Tanja Pejovic, Mian M.K. Shahzad, Marian S. Johnson, Mayu Yunokawa, Koji Matsuo, Munetaka Takekuma, Kohei Omatsu, Lynda D. Roman, Tsukasa Baba, Joseph L. Kelley, Yutaka Ueda, Sosuke Adachi, Takahito Miyake, Masato Nishimura, Kosei Hasegawa, Tadayoshi Nagano, Yuji Ikeda, Frederick R. Ueland, Dwight D. Im, Masako Shida, Shiori Yanai, Erin A. Blake, Stephen H. Bush, Hiroko Machida, Shinya Satoh, and Keita Iwasaki
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Oncology ,medicine.medical_specialty ,Breast Neoplasms ,Malignancy ,Lower risk ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Internal medicine ,medicine ,Humans ,Uterine Neoplasm ,Aged ,Neoplasm Staging ,Retrospective Studies ,Univariate analysis ,030219 obstetrics & reproductive medicine ,business.industry ,Estrogen Antagonists ,Obstetrics and Gynecology ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Confidence interval ,Tamoxifen ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,business ,medicine.drug - Abstract
OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I–IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P < 0.001) and had a past history of malignancy (100% versus 12.7%, P < 0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P = 0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P = 0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P = 0.48) and disease-specific survival (64.0% versus 59.1%, P =0.39).After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P =0.60)anddisease-specific survival(adjusted-hazard ratio0.68,95% confidence interval 0.36 to 1.29, P = 0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.
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- 2016
20. Prediction, based on resection margins, of long-term outcome of cervical intraepithelial neoplasia 3 treated by Shimodaira-Taniguchi conization
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Takashi Miyatake, Yukari Miyoshi, Yutaka Ueda, Masami Fujita, Hiroshi Ohashi, Eiichi Morii, Takuhei Yokoyama, Tadashi Kimura, Toshihiro Kimura, Takayuki Enomoto, Akiko Morimoto, Shinya Matsuzaki, and Kiyoshi Yoshino
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Adult ,Gynecology ,medicine.medical_specialty ,business.industry ,Conization ,Uterine Cervical Neoplasms ,Obstetrics and Gynecology ,General Medicine ,Middle Aged ,Prognosis ,Uterine Cervical Dysplasia ,Resection ,Young Adult ,Recurrence ,Cervical intraepithelial neoplasia 3 ,Humans ,Medicine ,Female ,Radiology ,business ,After treatment ,Aged - Abstract
The aim of the present study was to analyze the long-term outcome of cervical intraepithelial neoplasia 3 (CIN 3) after treatment with the Shimodaira-Taniguchi conization procedure, based on the status of the resection margins.In the Osaka University Hospital, conization using the Shimodaira-Taniguchi procedure has been routinely performed for CIN 3. Medical records of patients during the period from 2001 to 2008, whose post-conization diagnosis was CIN 3, were retrospectively analyzed for outcome versus margin status.During the median follow-up period of 565 days (range 34-3,013), CIN disease was again detected in 14 of 243 patients; it was found in 7 patients among 198 margin-negative cases, and in 7 patients among 45 margin-positive cases. There was a significant difference in the reappearance rate demonstrated between the cases with positive and negative margins (p = 0.0018). Among the patients whose first follow-up post-conization cytology was normal, recurrence-free probability was significantly higher in margin-negative cases than in margin-positive ones (hazard ratio, 5.19; 95% CI, 1.175-22.994; p = 0.0041).For the first time, we demonstrate that after treatment of CIN 3 lesions by Shimodaira-Taniguchi conization the status of the resection margin was a significant predictor for long-term outcome.
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- 2011
21. Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin
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Masami Fujita, Tadashi Kimura, Takahito Miyake, Yutaka Ueda, Shinya Matsuzaki, Kiyoshi Yoshino, Tomomi Egawa-Takata, Takayuki Enomoto, Takuhei Yokoyama, and Takashi Miyatake
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Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Paclitaxel ,Anthracycline ,medicine.medical_treatment ,Toxicology ,Second-line chemotherapy ,Disease-Free Survival ,Carboplatin ,chemistry.chemical_compound ,Endometrial cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Overall survival ,Pharmacology (medical) ,Epirubicin ,Retrospective Studies ,Pharmacology ,Chemotherapy ,Taxane ,business.industry ,Response ,Progression-free survival ,Combination chemotherapy ,Middle Aged ,medicine.disease ,Endometrial Neoplasms ,Regimen ,Treatment Outcome ,chemistry ,Multivariate Analysis ,Female ,Original Article ,Treatment-free interval ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline. Methods During the 2000–2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed. Results Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ≥ or
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- 2010
22. Endometrial carcinoma: better prognosis for asymptomatic recurrences than for symptomatic cases found by routine follow-up
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Tadashi Kimura, Yukari Miyoshi, Yutaka Ueda, Shinya Matsuzaki, Masami Fujita, Takuhei Yokoyama, Kiyoshi Yoshino, Takashi Miyatake, Takayuki Enomoto, and Tomomi Egawa-Takata
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medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Asymptomatic ,Disease-Free Survival ,Gynecologic Surgical Procedures ,Japan ,Predictive Value of Tests ,Surgical oncology ,Carcinoma ,medicine ,Humans ,Progression-free survival ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Endometrial cancer ,General surgery ,Retrospective cohort study ,Hematology ,General Medicine ,medicine.disease ,Endometrial Neoplasms ,Radiation therapy ,Treatment Outcome ,Oncology ,Chemotherapy, Adjuvant ,Predictive value of tests ,Female ,Radiotherapy, Adjuvant ,Surgery ,Radiology ,Neoplasm Recurrence, Local ,medicine.symptom ,business ,Carcinoma, Endometrioid - Abstract
The aim of this study was to determine if there is a prognostic value for the presence of symptoms at the time of recurrence detection in surgically resected endometrial carcinoma patients.During the study period of 2000-2006, complete surgical removal of endometrial carcinoma was achieved in 271 stage I-IV endometrial cancer cases at the Department of Obstetrics and Gynecology of Osaka University Hospital, Osaka, Japan. A subsequent recurrence was detected in 29 (11%) of these cases. Patient characteristics and clinicopathological features were retrospectively reviewed utilizing their clinical records.Among the 29 cases with a recurrence, 13 (45%) had symptoms, whereas in the other 16 cases (55%) the recurrent disease was found only during routine follow-up procedures. Although the time to detection of recurrence was similar for both asymptomatic and symptomatic cases, progression-free survival after detection in the 16 asymptomatic patients was significantly longer than for the 13 symptomatic patients (P = 0.017); this was found to be especially true in those who underwent chemotherapy as their adjuvant therapy (P = 0.023).A better prognosis after recurrence was demonstrated in cases that were asymptomatic at the time of recurrence detection than in those in which the tumor was symptomatic. This finding implies that, after the initial surgical resection, intensive follow-up intervention looking for asymptomatic recurrences may significantly improve the prognosis of endometrial carcinoma patients. A further in-depth prospective study is required to establish a standard strategy of follow-up care for endometrial cancer patients.
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- 2010
23. Mid-second trimester measurement of fetal nasal bone length in the Japanese population
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Masaaki Nagamatsu, Hirotsugu Fukuda, Takuhei Yokoyama, Mihyon Son, Hiroyuki Hashimoto, Yuji Murata, Yukiko Kinugasa, Koichiro Shimoya, Shigeyuki Isaka, and Takeshi Kanagawa
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Adult ,medicine.medical_specialty ,Adolescent ,Population ,Reference range ,Ultrasonography, Prenatal ,Japan ,Pregnancy ,Reference Values ,medicine ,Humans ,Nasal Bone ,education ,Fetus ,education.field_of_study ,business.industry ,Obstetrics ,Obstetrics and Gynecology ,Japanese population ,Nomogram ,Nasal bone ,medicine.disease ,Surgery ,Nomograms ,Gestation ,Female ,Down Syndrome ,business - Abstract
Aim: We carried out a preliminary study to compare the nasal bone length (NBL) and biparietal diameter/NBL (BPD/NBL) ratio between the Japanese and white populations. Methods: Three hundred and fifty nine (359) singleton fetuses of healthy Japanese couples were examined from June 2004 to October 2005. NBL was measured by the strict midsagittal section. The reference range of NBL was established from cross-sectional data between 15 and 25 weeks’ gestation. Results: The success rate of obtaining reliable NBL was 93% (333/356). There were 330 fetuses (93%) available for constructing a reference range from the population. The median NBL increased from 3.2 mm at 15 weeks’ to 7.6 mm at 25 weeks’ gestation. The median of BPD/NBL ratio was 9.01. Conclusions: We demonstrated that NBL was significantly shorter and BPD/NBL was significantly greater in the Japanese population than those in the white and black populations.
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- 2006
24. Abstract 4410: LSR promotes ovarian cancer cell growth following the activation of β-oxidation and its antibody inhibits lipid catabolism
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Tetsuji Naka, Minoru Fujimoto, Tadashi Kimura, Takuhei Yokoyama, Kosuke Hiramatsu, Takayuki Enomoto, Yusuke Takahashi, Satoshi Serada, and Kiyoshi Yoshino
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Cancer Research ,Oncology ,Biochemistry ,biology ,Lipid catabolism ,Cell growth ,biology.protein ,medicine ,Cancer research ,Antibody ,Ovarian cancer ,medicine.disease - Abstract
Ovarian cancer is the most lethal gynecologic malignancy; thus developing new treatment options is urgently required. Molecular targeted therapies for cancers, which are generally more tolerable than widely used cytotoxic agents, have shown highly specific inhibition of target molecules. In this study, we aimed to identify a new ovarian cancer antigen and to develop a novel monoclonal antibody (mAb). Furthermore we evaluated its preclinical efficacy and analyzed the function of its antigen in ovarian cancer.To identify a new ovarian cancer antigen, cell surface membrane proteins of normal ovarian epithelial and ovarian cancer cell lines were analyzed by iTRAQ-based proteomic technology. We identified lipolysis-stimulated lipoprotein receptor (LSR) as the new therapeutic target for ovarian cancer. By the immunohistochemical analysis, significant poor prognosis was observed in high-LSR expression patients with ovarian cancer compared to patients with low-LSR expression by survival assay (p < 0.05). Our newly developed anti-LSR mAb showed significant inhibition of tumor growth in vivo against xenograft model of LSR-positive ovarian cancer cell line and patient derived LSR-positive ovarian cancer tissue (p < 0.05). In LSR-positive ovarian cancer cells, high number and large lipid droplets were observed compared to LSR-negative cells and anti-LSR mAb decreased these droplets. Moreover addition of VLDL to LSR-positive ovarian cancer cells significantly promoted the cell proliferation (p < 0.05) and anti-LSR mAb inhibited that in vitro (p < 0.05). Supporting these data, addition of VLDL to LSR-positive ovarian cancer cells significantly promoted β-oxidation-mediated lipid catabolism (p < 0.05) and anti-LSR mAb also inhibited that (p < 0.05). In addition, this anti-LSR mAb which cross-reacted with mouse LSR did not show any cytotoxicity on normal organs and lipid metabolism in mice. In summary, high expression of LSR in ovarian cancer was the poor prognostic factor. Our newly developed anti-LSR mAb showed significant tumor growth inhibition against not only LSR-positive ovarian cancer cell line but also patient derived LSR-positive ovarian cancer tissue. In LSR-positive ovarian cancer cells, high number and large lipid droplets were observed and LSR promoted cell proliferation following β-oxidation-mediated lipid catabolism. Anti-LSR mAb inhibited these processes. Our preclinical data demonstrated that targeting LSR by mAb is a promising therapy for patients with LSR-positive ovarian cancer. Citation Format: Kosuke Hiramatsu, Satoshi Serada, Takayuki Enomoto, Takuhei Yokoyama, Yusuke Takahashi, Minoru Fujimoto, Kiyoshi Yoshino, Tadashi Kimura, Tetsuji Naka. LSR promotes ovarian cancer cell growth following the activation of β-oxidation and its antibody inhibits lipid catabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4410. doi:10.1158/1538-7445.AM2017-4410
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- 2017
25. Pedunculated Sub-Serous Leiomyosarcoma Mimicking Ovarian Cancer: Case Report and Review of Literature
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Takuhei Yokoyama, Kiyoshi Yoshino, Yutaka Ueda, Masami Fujita, Yumiko Hori, Satoshi Nakagawa, Eiichi Morii, Shinya Matsuzaki, Toshihiro Kimura, and Tadashi Kimura
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Leiomyosarcoma ,Pathology ,medicine.medical_specialty ,Malignant Ovarian Tumor ,business.industry ,Uterine leiomyosarcoma ,Uterine fundus ,medicine.disease ,body regions ,Serous fluid ,Medicine ,Radiology ,Differential diagnosis ,business ,Ovarian cancer - Abstract
Pedunculated subserous leiomyosarcoma is a quite rare presentation of leiomyosarcoma. As of 2013, only three cases have been reported in the literature. In this case report, we document two new cases of pedunculated subserous leiomyosarcoma from uterine fundus. These two cases illustrate the difficulty of making a correct differential diagnosis between a pedunculatedsubserous uterine leiomyosarcoma and a malignant ovarian tumor before intervention. A review of the literature confirms that this site remains unusual and making the diagnosis is difficult.
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- 2013
26. Abstract 264: The cell cycle checkpoint kinase 1/2 inhibitor, LY2606368 with PARP inhibition results in synergistic cytotoxicity in high-grade serous ovarian cancer (HGSOC) at lower than physiologically administered concentrations
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Minshu Yu, Yeong-ran Ahn, Nicolas Gordon, Jung-Min Lee, Takuhei Yokoyama, and Elise C. Kohn
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Cancer Research ,medicine.medical_specialty ,DNA damage ,DNA repair ,Poly ADP ribose polymerase ,Cell cycle ,Biology ,Olaparib ,Comet assay ,chemistry.chemical_compound ,Endocrinology ,Oncology ,chemistry ,Internal medicine ,medicine ,Cancer research ,CHEK1 ,Cytotoxicity - Abstract
Background: Chk1/2 are major cell cycle regulators in p53-deficient tumors, such as HGSOC. Chk1 plays a critical role in DNA repair, facilitating the BRCA2-RAD51 interaction by phosphorylating the BRCA2 C-terminal domain and Thr309-RAD51. Clinical activity with the Chk1/2 inhibitor, LY2606368 mesylate monohydrate (LY), has been observed in solid tumors. We hypothesize that Chk1 inhibition would sensitize HGSOC to PARP inhibition (PARPi) by preventing nuclear RAD51 foci formation, thus impairing DNA repair. We investigated potential synergy of the combination of LY and the PARPi, olaparib (O), in HGSOC cell lines, testing lower concentrations than clinically attained. Materials and Methods: We examined cytotoxicity, DNA damage, and nuclear RAD51 foci formation by LY and/or O using XTT assay, comet assay and immunofluorescence (IF), in 3 HGSOC cell lines: two BRCA1/2 wild type (CAOV3, OV90), and one with BRCA2 mutation (PEO1). We examined a dose range based on clinically achievable concentrations of LY (0.53μM–1.34μM) and O (7.8μM–11.0μM) and calculated IC50 concentrations for cytotoxicity. The combination index (CI) was calculated to evaluate synergism. DNA damage and nuclear RAD51 foci formation were examined. DMSO was used as vehicle control. All experiments were performed in at least three replicates in all cell lines. Results are presented as mean ± SEM. Results: LY alone yielded cytotoxicity in CAOV3, OV90, and PEO1 with IC50 6.34nM, 35.2nM, 12.6nM, respectively. O 5μM monotherapy resulted in 47%, 13%, and 69% cytotoxicity in CAOV3, OV90, and PEO1. LY/O combination showed 51%, 58% and 82% cell injury in CAOV3, OV90 and PEO1. CI values indicated cytotoxicity synergism with the combination. LY/O (5nM/5μM) treatment showed greater DNA damage than O alone in OV90 and PEO1 (p Conclusions: Our preliminary results suggest synergistic activity of the combination of LY and PARPi in HGSOC cell lines using concentrations that are lower than clinically attainable in patients. Citation Format: Yeong-ran Ahn, Takuhei Yokoyama, Minshu Yu, Nicolas Gordon, Elise C. Kohn, Jung-min Lee. The cell cycle checkpoint kinase 1/2 inhibitor, LY2606368 with PARP inhibition results in synergistic cytotoxicity in high-grade serous ovarian cancer (HGSOC) at lower than physiologically administered concentrations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 264.
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- 2016
27. Biomarkers for screening, diagnosis, and monitoring of ovarian cancer
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Takayuki Enomoto, Yutaka Ueda, Takuhei Yokoyama, Shinya Matsuzaki, Masami Fujita, Kiyoshi Yoshino, Eiji Kobayashi, Toshihiro Kimura, and Tadashi Kimura
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Oncology ,medicine.medical_specialty ,Epidemiology ,Population ,Proteomics ,Asymptomatic ,Serum biomarkers ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Mass Screening ,Stage (cooking) ,education ,Early Detection of Cancer ,Ovarian Neoplasms ,education.field_of_study ,business.industry ,Cancer ,medicine.disease ,Female ,medicine.symptom ,Ovarian cancer ,business ,Serum markers - Abstract
Serum tumor markers have a major role in the screening, diagnosis, and monitoring of most of the gynecologic cancers. Ovarian cancer is one of the deadliest of the group because it is so frequently asymptomatic until it has advanced to an untreatable stage. Even serum cancer antigen-125 (CA-125), clinically one of the most reliable serum markers for ovarian cancer, is elevated in only half of early-stage still-treatable tumors. Because of the very low prevalence of ovarian cancer in the general population, at present, there is no cost-effective imaging or simple microscopic screening test for ovarian cancer as there is for breast and cervical cancers. However, recent proteomics and nucleic acid–based analyses have shown great promise for the discovery of new and more useful serum biomarkers, which cumulatively might provide such a screening tool. In this review, we will discuss both the currently used serum tumor markers for screening, diagnosis, monitoring of ovarian cancer, and the novel biomarkers that are now under investigation and validation. Cancer Epidemiol Biomarkers Prev; 21(11); 1902–12. ©2012 AACR.
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- 2012
28. Salvage chemotherapy for ovarian carcinoma recurring during or after consolidation chemotherapy with paclitaxel
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Yukari, Miyoshi, Yutaka, Ueda, Akiko, Morimoto, Takuhei, Yokoyama, Shinya, Matsuzaki, Eiji, Kobayashi, Toshihiro, Kimura, Kiyoshi, Yoshino, Masami, Fujita, Takayuki, Enomoto, and Tadashi, Kimura
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Adult ,Ovarian Neoplasms ,Salvage Therapy ,Time Factors ,Paclitaxel ,Carcinoma ,Middle Aged ,Irinotecan ,Disease-Free Survival ,Treatment Outcome ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Camptothecin ,Female ,Cisplatin ,Aged ,Retrospective Studies - Abstract
The aim of the study was to analyze the effectiveness of salvage chemotherapy for recurring ovarian carcinoma during or after consolidation chemotherapy.During the study period, 12 patients received salvage chemotherapy for recurrence during or after consolidation chemotherapy. These cases were retrospectively reviewed.The response rate for salvage chemotherapy was 67% and was significantly associated with treatment-free interval (TFI) after consolidation (p=0.038). Progression-free survival was also significantly related to TFI (p=0.032). Combination chemotherapy of cisplatin plus irinotecan was effective in all five cases with TFI≥6 months and in three out of seven cases with TFI6 months.Our study provides, for the first time, evidence that effectiveness of salvage chemotherapy for recurrent ovarian carcinoma occurring during or after consolidation chemotherapy can be predicted by TFI, and that combination chemotherapy of cisplatin plus irinotecan is potentially useful for these cases.
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- 2011
29. Disease-free interval after primary treatment predicts prognosis of recurrent endometrial carcinoma
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Yutaka, Ueda, Yuki, Matsumura, Tomomi, Egawa-Takata, Takahito, Miyake, Takashi, Miyatake, Kiyoshi, Yoshino, Masami, Fujita, Shinya, Matsuzaki, Takuhei, Yokoyama, Yukari, Miyoshi, Masato, Yamasaki, Takayuki, Enomoto, and Tadashi, Kimura
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Adult ,Aged, 80 and over ,Middle Aged ,Disease-Free Survival ,Endometrial Neoplasms ,Survival Rate ,Chemotherapy, Adjuvant ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Radiotherapy, Adjuvant ,Neoplasm Recurrence, Local ,Aged ,Proportional Hazards Models ,Retrospective Studies - Abstract
The aim of this study was to determine if the disease-free interval after initial surgical resection has any useful prognostic value for recurrent endometrial carcinoma patients.Between 1998 and 2007, complete resection of endometrial carcinoma was achieved in 536 cases at the Departments of Obstetrics and Gynecology of the Osaka University and Osaka Rosai Hospitals of Osaka, Japan. Clinical characteristics of these cases were retrospectively reviewed.Recurrence was subsequently detected in 54 cases. Overall survival after recurrence in 27 patients with recurrences earlier than 12 months who received no postoperative therapy, radiation, and chemotherapy as an adjuvant therapy were significantly shorter than that of those with recurrences later than 12 months with similar treatments. Multivariate analysis demonstrated that the disease-free interval was an independent factor for prognosis.We demonstrate a significantly worse prognosis in cases with early versus late recurrence of resected endometrial carcinomas, irrespective of the type of adjuvant therapy.
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- 2010
30. Recurrent endometrial carcinoma: prognosis for patients with recurrence within 6 to 12 months is worse relative to those relapsing at 12 months or later
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Yukari Miyoshi, Masami Fujita, Masato Yamasaki, Tadashi Kimura, Tomomi Egawa-Takata, Toshihiro Kimura, Takuhei Yokoyama, Kiyoshi Yoshino, Takayuki Enomoto, Yutaka Ueda, Takahito Miyake, and Shinya Matsuzaki
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medicine.medical_specialty ,Time Factors ,Anthracycline ,medicine.medical_treatment ,chemistry.chemical_compound ,Carcinoma ,medicine ,Humans ,In patient ,Retrospective Studies ,Chemotherapy ,Taxane ,business.industry ,Endometrial cancer ,Obstetrics and Gynecology ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Carboplatin ,Surgery ,Endometrial Neoplasms ,chemistry ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Objective We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs). Study Design We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC). Results Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months). Conclusion Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy.
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- 2010
31. Abstract 4382: Anti-human LSR monoclonal antibody inhibits tumor growth of ovarian cancer directly
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Minoru Fujimoto, Akiko Morimoto, Yutaka Ueda, Tetsuji Naka, Takuhei Yokoyama, Eiichi Morii, Satoshi Nakagawa, Kosuke Hiramatsu, Yusuke Takahashi, Satoshi Serada, Takayuki Enomoto, Tadashi Kimura, and Kiyoshi Yoshino
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Antibody-dependent cell-mediated cytotoxicity ,Cancer Research ,medicine.drug_class ,business.industry ,Endometrial cancer ,Cancer ,Cell cycle ,Monoclonal antibody ,medicine.disease ,Oncology ,Antigen ,Immunology ,medicine ,Cancer research ,Immunohistochemistry ,Ovarian cancer ,business - Abstract
Ovarian cancer is the most lethal gynecologic malignancy; thus developing new treatment options is urgently required. Molecular targeted therapies for cancers, which are generally more tolerable than widely used cytotoxic agents, have shown highly specific inhibition of target molecules. We previously identified bone marrow stromal antigen 2 (BST2) as an endometrial cancer antigen using iTRAQ-based quantitative proteomic technology focused on cell surface membrane proteins, and also demonstrated the usefulness of an anti-BST2 monoclonal antibody (mAb) for endometrial cancer. In this study, we aimed to identify a new ovarian cancer antigen. We also aimed to develop a novel monoclonal antibody (mAb) and evaluate its preclinical efficacy against ovarian cancer. To identify a new ovarian cancer antigen, cell surface membrane proteins of normal ovarian epithelial and ovarian cancer cell lines were analyzed by iTRAQ-based proteomic technology. As the new therapeutic target for ovarian cancer, we identified lipolysis-stimulated lipoprotein receptor (LSR) which had one of the largest significant differences in protein level between normal ovarian epithelial and ovarian cancer cell lines. Immunohistochemical analysis showed that the overall survival of ovarian serous carcinoma patients with high LSR expression was significantly shorter than those with low LSR (p = 0.0293). We newly developed anti-LSR mAb and investigated its preclinical efficacy. Anti-LSR mAb showed significant in vivo inhibition of tumor growth against a xenograft model of hLSR-positive ovarian cancer in an antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) independent manner (p = 0.0001). And anti-LSR mAb also induced G0/G1 cell cycle arrest by regulation of MEK and p44/42 MAPK activities and expression levels of cell cycle related proteins in vitro. Furthermore, anti-hLSR mAb, which crossreacts with mouse LSR, had little detectable toxicity in mice. In summary, high expression of LSR in ovarian cancer was the poor prognostic factor. Our newly developed anti-LSR mAb showed significant tumor growth inhibition in ADCC and CDC independent manner in vivo. Anti-human LSR mAb also inhibited LSR function and showed direct tumor growth inhibition inducing G0/G1 cell cycle arrest in vitro. Our preclinical data demonstrated that targeting LSR by mAb is a promising therapy for patients with LSR-positive ovarian cancer. Citation Format: Kosuke Hiramatsu, Satoshi Serada, Takayuki Enomoto, Satoshi Nakagawa, Akiko Morimoto, Minoru Fujimoto, Takuhei Yokoyama, Yusuke Takahashi, Yutaka Ueda, Kiyoshi Yoshino, Eiichi Morii, Tadashi Kimura, Tetsuji Naka. Anti-human LSR monoclonal antibody inhibits tumor growth of ovarian cancer directly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2015-4382
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- 2015
32. Abstract 5363: Navitoclax (Nav) and BMN 673 yield cytotoxicity with lower doses than used for single agents in high-grade serous ovarian cancer (HGSOC)
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Jung-Min Lee, Takuhei Yokoyama, Nicolas Gordon, Minshu Yu, and Elise C. Kohn
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Cancer Research ,Navitoclax ,Cancer ,medicine.disease ,Carboplatin ,Olaparib ,Comet assay ,chemistry.chemical_compound ,Oncology ,chemistry ,Apoptosis ,PARP inhibitor ,Immunology ,Cancer research ,medicine ,Cytotoxicity - Abstract
Background: The apoptosis inhibitor Bcl-xL is upregulated in recurrent ovarian cancer (OvCa). Modest clinical activity with Nav, a Bcl-2/Bcl-xL inhibitor, was observed in hematologic malignancies, although significant thrombocytopenia has been a challenge to its development. BMN 673 is a PARP inhibitor (PARPi) and is more potent at a molar level than other PARPi in preclinical studies. We observed a decrease in Bim and Bcl-2 protein expression in OvCa tissue after 1 cycle of olaparib (PARPi) and carboplatin compared to pretreatment levels; this change correlated with duration of response in BRCA1/2 mutation-related breast and OvCa patients (r2 = -0.86, p Methods: We examined cell injury, DNA damage, and apoptosis by XTT, comet assay, and caspase-3 activity in two HGSOC cell lines, CAOV3 and OVCAR8. We examined a dose range based on clinically achievable concentrations of Nav (1-8 μM) and BMN 673 (25-100 nM) and calculated IC50 concentrations for cytotoxicity. 2 μM Nav and 50 nM BMN 673 were selected to examine alone and in combination measures of DNA damage and apoptosis. Controls were cells with no treatment for comet assay, and with DMSO vehicle control for caspase-3 activity. The combination index (CI) was calculated to evaluate synergism. All experiments were performed in at least 3 replicates in all cell lines. Results are presented as mean ± SEM. Result: Nav yielded cytotoxicity in CAOV3 and OVCAR8 cells with IC50 2.67 μM and 4.39 μM, respectively. BMN 673 100 nM monotherapy yielded up to 40% cell injury in CAOV3 and 20% in OVCAR8 cells. The combination of BMN 673 50 nM and Nav 2 μM resulted in more than 80% and 30% cell injury in CAOV3 and OVCAR8, respectively. The CI indicates there is synergism in cell injury between the two drugs at or below clinically attainable concentrations. BMN 673 alone and with Nav augmented% DNA in tail in an additive fashion, over control or Nav alone in both cell lines. The effect with the combination v. Nav alone was significant in OVCAR8 (12.74% +/- 0.38 v. 9.49% +/- 0.55, p Conclusion: Our preliminary results suggest that the combination of PARP inhibition and Bcl2/Bcl-xL neutralization may be cooperative in yielding better results than either drug alone in HGSOC. Further experiments are currently underway to evaluate this novel drug combination. Citation Format: Takuhei Yokoyama, Nicolas Gordon, Minshu Yu, Elise C. Kohn, Jung-Min Lee. Navitoclax (Nav) and BMN 673 yield cytotoxicity with lower doses than used for single agents in high-grade serous ovarian cancer (HGSOC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5363. doi:10.1158/1538-7445.AM2015-5363
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- 2015
33. Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP.
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TAKUHEI YOKOYAMA, KOHN, ELISE C., BRILL, ETHAN, and JUNG-MIN LEE
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- 2017
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34. Abstract 4057: Functional domain of Annexin A4: which domain is indispensable for chemoresistance to platinum drugs
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Masami Fujita, Takayuki Enomoto, Takuhei Yokoyama, Tetsuji Naka, Akiko Morimoto, Kousuke Hiramatsu, Tadashi Kimura, Satoshi Serada, Shinya Matsuzaki, Kiyoshi Yoshino, and Yutaka Ueda
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Cisplatin ,Cancer Research ,Cancer ,Transfection ,Biology ,medicine.disease ,Bioinformatics ,Carboplatin ,chemistry.chemical_compound ,Oncology ,chemistry ,Annexin ,Cell culture ,Cancer research ,medicine ,MTT assay ,Ovarian cancer ,medicine.drug - Abstract
Background: Platinum drugs are often used for the postoperative adjuvant therapy or treatment in advanced and recurrent ovarian cancer. We have previously reported that ovarian clear cell carcinoma (CCC) has increased expression of Annexin A4 (Anx A4) in comparison with other subtype of ovarian cancer. Enhanced expression of Anx A4 has been shown to induce chemoresistance via extracellular efflux of carboplatin. Purpose: To identify the domain of Anx A4 relevant to chemoresistance. Materials and methods: Anx A4 possesses the NH2-terminal domain and four annexin repeat domains with one Ca2+-binding site in each domain. Deleting annexin repeat domains one by one from C-terminal site, we generated four deletion mutants of Anx A4 named R1, 2, 3, and 4 (arabic figure shows the number of annexin repeat domains). Stable cell lines overexpressing each deletion mutants were established in NUGC3 cells. Chemosensitivity to platinum drugs was evaluated using the MTT assay. Results. Compared with mock transfected cells, all the four deletion mutants induced chemoresistance to both cisplatin and carboplatin. Conclusions. The deletion derivative covering only one annexin repeat domain can induce chemoresistance to platinum drugs. Further study is underway to determine the specific site for chemoresistance of Anx A4. Citation Format: Akiko Morimoto, Takayuki Enomoto, Shinya Matsuzaki, Kousuke Hiramatsu, Yutaka Ueda, Kiyoshi Yoshino, Masami Fujita, Takuhei Yokoyama, Satoshi Serada, Tetsuji Naka, Tadashi Kimura. Functional domain of Annexin A4: which domain is indispensable for chemoresistance to platinum drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4057. doi:10.1158/1538-7445.AM2013-4057
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- 2013
35. Abstract 4059: Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A
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Tadashi Kimura, Yutaka Ueda, Kiyoshi Yoshino, Tetsuji Naka, Takuhei Yokoyama, Masami Fujita, Takayuki Enomoto, Akiko Morimoto, Satoshi Serada, Eiji Kobayashi, Shinya Matsuzaki, and Toshihiro Kimura
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Cisplatin ,Cancer Research ,Small interfering RNA ,ATP7A ,Biology ,Carboplatin ,In vitro ,chemistry.chemical_compound ,Oncology ,chemistry ,In vivo ,Annexin ,Immunology ,medicine ,Cancer research ,Efflux ,medicine.drug - Abstract
Because platinum drugs are often used for the chemotherapy of human cancers, when platinum resistance occurs it is a major issue. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to Carboplatin via increased extracellular efflux of the drug. However, the precise mechanisms of that chemoresistance, and the relationship of Anx A4 to platinum resistance in vivo, remain unclear. In this report we investigate in vitro the mechanism of platinum resistance induced by Anx A4 in endometrial carcinoma cells (HEC1 cells) which normally have a low level of expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, we compared HEC1 control cells with Anx A4-overexpressing HEC1 cells when both were xenografted to mice, Anx A4-overexpressing xenografted mice presented with significantly greater chemoresistance to Cisplatin in vivo. By immunofluorescence analysis we found that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became co-localized with ATP7A, a copper transporter also well known to be a platinum effluxer. When the expression of ATP7A was suppressed by small interfering RNA in HEC1 control cells, they showed no change of chemosensitivity to platinum drugs. However, suppressed ATP7A in Anx A4 overexpressing platinum-resistant cells, they showed improved chemosensitivity to platinum drugs, to a level comparable of that of control cells. Our results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A. Citation Format: Shinya Matsuzaki, Akiko Morimoto, Satoshi Serada, Takuhei Yokoyama, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Masami Fujita, Takayuki Enomoto, Tetsuji Naka, Tadashi Kimura. Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4059. doi:10.1158/1538-7445.AM2013-4059
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- 2013
36. Abstract 4363: Silencing of JAM-A inhibits cell growth through cell cycle arrest in endometrial cancer
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Kiyoshi Yoshino, Tadashi Kimura, Masami Fujita, Takayuki Enomoto, Tetsuji Naka, Satoshi Serada, Takuhei Yokoyama, Kousuke Hiramatsu, Akiko Morimoto, and Yutaka Ueda
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Cancer Research ,Pathology ,medicine.medical_specialty ,Cell cycle checkpoint ,medicine.diagnostic_test ,Cell growth ,Endometrial cancer ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,humanities ,Tumor antigen ,Flow cytometry ,Oncology ,Cell culture ,medicine ,Cancer research ,Carcinogenesis - Abstract
Endometrial cancer is one of the most common malignancies of the female genital tract. The identification of proteins for prognostic assessment and therapeutic targets in this disease is of significant clinical importance. We have previously reported a novel proteomic method for discovering potential therapeutic targets in endometrial cancer. We used a biotinylation-based approach for cell-surface protein enrichment combined with isobaric tags for relative and absolute quantitation (iTRAQ) technology using nano liquid chromatography-tandem mass spectrometry analysis to identify specifically overexpressed proteins in endometrial cancer cells compared with normal endometrial cells. We identified a total of 272 proteins, including 11 plasma membrane proteins, whose expression was increased more than twofold in at least four of seven endometrial cancer cell lines compared with a normal endometrial cell line. In addition to the identification of previously reported tumor antigens such as NCAML1, we also identified JAM-A as a novel tumor antigen in endometrial cancer by this methodology. JAM-A is a member of the immunoglobulin superfamily found at intercellular junctions of endothelial cells and epithelial cells. Some investigators have studied the role of JAM-A in carcinogenesis. However, the role of JAM-A in tumor growth and dissemination is still a debated issue. In this study, our goal is to investigate the role of JAM-A in tumor growth as well as the potential value in cancer therapeutic target. To confirm the altered expression of JAM-A in endometrial cancer, we performed flow cytometry and western blotting analysis using one immortalized normal endometrial cells (EM-E6/E7/TERT) and nine endometrial cancer cell lines (HEC-1, HEC-1A, HEC-6, HEC-88nu, HEC-108, HEC-116, SNG-II, and SNG-M). Protein expression of JAM-A was not detected in normal endometrial cells. In contrast, a considerably higher level of JAM-A expression was detected in all the nine endometrial cancer cell lines. Furthermore, to test the functional significance of JAM-A in endometrial cancer cell proliferation, the effect of JAM-A siRNA treatment was evaluated using WST-8 assay. Compared with non-target siRNA control, siRNA targeting JAM-A dramatically inhibits endometrial cancer cell proliferation. Flow cytometry with propidium iodide-staining revealed that JAM-A siRNA treatment induces cell cycle arrest in endometrial cancer cells. Taken together, our findings suggest that JAM-A may play a regulatory role in proliferation of endometrial cancer cells. Further studies are underway to identify the signal transduction pathway involved in JAM-A siRNA induced growth inhibition. Citation Format: Takuhei Yokoyama, Takayuki Enomoto, Kousuke Hiramatsu, Akiko Morimoto, Yutaka Ueda, Kiyoshi Yoshino, Masami Fujita, Tadashi Kimura, Satoshi Serada, Tetsuji Naka. Silencing of JAM-A inhibits cell growth through cell cycle arrest in endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4363. doi:10.1158/1538-7445.AM2013-4363
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- 2013
37. Abstract 4257: Establishment of cancer-tissue originated spheroids (CTOSs) and chemo-sensitivity test for endometrial cancer
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Eiji Kobayashi, Kosuke Hiramatsu, Masami Fujita, Takayuki Enomoto, Masahiro Inoue, Yutaka Ueda, Toshihiro Kimura, Takuhei Yokoyama, Akiko Morimoto, Yumiko Kiyohara, Tadashi Kimura, and Kiyoshi Yoshino
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Endometrial cancer ,Pathological staging ,Cancer ,medicine.disease ,Malignancy ,Internal medicine ,Cancer cell ,medicine ,Histopathology ,business ,medicine.drug - Abstract
[Background] Endometrial cancer is one of the most common malignancy of the female genital tract in Japan, and the frequency is increasing year by year. Surgical therapy is performed as initial treatment for most of the patients. Pathological staging according to the surgical findings and the pathological findings is the most important prognostic factors. Several trials of adjuvant radiation and/or chemotherapy have been conducted for high-risk patients, but so far no standard regimen is confirmed. In this study, we established a chemo-sensitivity test for endometrial cancer using cancer-tissue originated spheroids (CTOSs). This chemo-sensitivity test can find not only the best regimen for endometrial cancer but also personalized medicine in the future. [Materials and Methods] A new primary culture system has been reported in colon cancer. These cells are called CTOS (cancer-tissue originated spheroids), in which cell-cell contact of cancer cells is retained throughout the process. By the CTOS method, highly purified and viable primary colorectal cancer cells are effectively prepared and cultured in vitro. Fresh cancerous tissues were removed from a series of 10 patients with endometrial cancer. Surgical and pathological findings revealed that 6 cases were Stage I, 1 case was Stage II, 3 cases were Stage III, 0 case was Stage IV. For histological classification, all of them were endometrioid adenocarcinoma (G1; 4 cases, G2; 4 cases, G3; 2 cases). Cancer tissues were removed and prepared as previously described by Kondo et al (PNAS, 2011). Briefly, primary culture cells are purified from the surgical specimen by mechanical and chemical treatment steps. These cells formed spheroids within 24 hours and can be cultured and expanded in stem cell culture medium. [Results] In our study, by day 14 spheroid formation was observed in 6 out of 10 cases (60%). Some of these spheroids were transplanted to subcutaneous of immune-deficient mice and formed tumors. These xenograft tumors showed quite similar appearance for their histopathology in comparison with their original tumor. For chemo-sensitivity test, spheroids were cultured in the medium with cisplatin at the day 7. The medium was changed at the day 8 exposing CTOSs to cisplatin for 1 day. The spheroids growth was inhibited in a dose-dependent manner. [Conclusion] For endometrial cancer, establishment of CTOSs allow us to analyze chemo-sensitivity as primary culture in high success rate. This approach gives a prediction of the efficacy of anti-cancer agents for personalized medicine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4257. doi:1538-7445.AM2012-4257
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- 2012
38. Abstract 4225: Annexin A4 induces chemoresistance for multiple drugs in ovarian clear cell carcinoma
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Shinya Matsuzaki, Kiyoshi Yoshino, Masami Fujita, Yutaka Ueda, Akiko Morimoto, Satoshi Serada, Takuhei Yokoyama, Takayuki Enomoto, Toshihiro Kimura, Tetsuji Naka, Minoru Fujimoto, and Tadashi Kimura
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Gene knockdown ,business.industry ,Cancer ,medicine.disease ,Carboplatin ,chemistry.chemical_compound ,chemistry ,Annexin ,Internal medicine ,Clear cell carcinoma ,medicine ,Adjuvant therapy ,Ovarian cancer ,business ,medicine.drug - Abstract
BACKGROUND: Platinum drugs play the key role for postoperative adjuvant therapy and treatment in progress and recurrent ovarian cancer. We have previously reported that ovarian clear cell carcinoma (CCC) has increased expression of Annexin A4 (Anx A4) in comparison with other subtypes of ovarian cancer. Enhanced expression of Anx A4 has been shown to induce chemoresistance via extracellular efflux of carboplatin. However, it remains unclear whether targeting Anx A4 is effective for improving the sensitization against chemotherapy, like platinum drugs. The aim of this study was to evaluate the role of Anx A4 in chemoresistance in ovarian CCC. MATERIAL AND METHODS: RMG-I cell lines were used to establish the stable knockdown of Anx A4. Plasmids encoding short hairpin RNAs (shRNAs) targeting Anx A4 were transfected. Chemoresistance was assessed by IC50 value in various drugs. RESULTS: Compared with control cells, knockdown of Anx A4 gene expression in RMG-I cells induced chemosentisitzation around 2-fold to cisplatin (IC50: 11.2 μM to 5.8 μM, P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4225. doi:1538-7445.AM2012-4225
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- 2012
39. Abstract 5108: Quantitative proteomic analysis of cell-surface membrane proteins: Biomarker discovery in endometrial cancer
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Ayako Kim, Masami Fujita, Kiyoshi Yoshino, Yutaka Ueda, Toshihiro Kimura, Satoshi Serada, Takuhei Yokoyama, Shinya Matsuzaki, Tetsuji Naka, Minoru Fujimoto, Tadashi Kimura, and Takayuki Enomoto
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Cancer Research ,Endometrial cancer ,Cancer ,Cell migration ,Biology ,medicine.disease ,Bioinformatics ,Cell membrane ,medicine.anatomical_structure ,Oncology ,Membrane protein ,Antigen ,Biotinylation ,medicine ,Cancer research ,Biomarker discovery - Abstract
Background. Endometrial cancer is one of the most common malignancies of the female genital tract. The identification of proteins for prognostic assessment and therapeutic targets in this disease is of significant clinical importance. Quantitative proteomic analysis provides a powerful approach in screening for alterations in protein levels and post-translational modifications that are associated with tumors. To date, proteomic studies of cancer have focused particularly on sub-cellular compartments or post-translational modifications. An analysis of the differential expression of cell-surface membrane proteins would be of particular interest, since these proteins play key roles in cell function including cell migration and drug resistance. Purpose of study. To identify membrane proteins overexpressed in endometrial cancer which may represent novel biomarkers of disease and therapeutic targets. Procedures. We developed a biotinylation-based approach for cell membrane enrichment combined with iTRAQ (isobaric tags for relative and absolute quantitation) technology using nano-LC-MS/MS analysis, to identify cell surface proteins overexpressed in seven endometrial cancer cell lines compared with a control normal endometrial cell line. Results. 365 proteins were identified, of which, 65 proteins (18%) possessed a trans-membrane domain. We identified overexpression of 24 membrane proteins in endometrial cancer cell lines compared with a normal endometrial cell line. By this proteomic approach, we identified several tumor antigens which included antigens previously associated with endometrial cancer and antigens not previously reported in this disease. Tumorigenic proteins such as neural cell adhesion molecule L1 (NCAML1), previously reported to be overexpressed in endometrial cancer, were identified. Interestingly we also identified Claudin-4, a protein associated with poor prognosis in various cancers, but not previously reported in the pathogenesis of cancer. In addition, we also successfully identified novel antigens associated with endometrial cancer. Conclusions. We developed a high throughput cell-surface membrane proteomic analysis combining biotinylation of cell-surface membrane protein and iTRAQ technology. In addition to the identification of previously reported tumor antigens such as NCAML1 and Claudin-4, we also identified novel tumor antigens in endometrial cancer by this methodology. This iTRAQ based quantitative proteomic analysis represented a useful approach in screening for novel disease biomarkers and therapeutic targets. Further studies on the physiological role of novel tumor antigens overexpressed in endometrial cancer and their application as biomarkers/therapeutic targets are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5108. doi:10.1158/1538-7445.AM2011-5108
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- 2011
40. Characterizing sarcoma dominance pattern in uterine carcinosarcoma: Homologous versus heterologous element.
- Author
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Koji Matsuo, Yutaka Takazawa, Ross, Malcolm S., Elishaev, Esther, Mayu Yunokawa, Sheridan, Todd B., Bush, Stephen H., Klobocista, Merieme M., Blake, Erin A., Tadao Takano, Tsukasa Baba, Shinya Satoh, Masako Shida, Yuji Ikeda, Sosuke Adachi, Takuhei Yokoyama, Munetaka Takekuma, Shiori Yanai, Satoshi Takeuchi, and Masato Nishimura
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CARCINOSARCOMAS , *UTERINE cancer , *RADIOTHERAPY , *CANCER chemotherapy , *PROGNOSIS , *METASTASIS , *DISEASE progression , *UNIVARIATE analysis - Abstract
Objective To examine significance of sarcoma dominance (SD) patterns in uterine carcinosarcoma (UCS). Methods This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. Results SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35-1.69, and hetero/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). Conclusion In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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