論文 - 大家　基嗣

Expression of Ets-1 in human clear cell renal cell carcinomas

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Murai Masaru, Mukai Makio, Okada Yasunori

Cancer Science 97 （ 9 ） 875 - 882 2006年09月

ISSN  1347-9032

　概要を見る

<p>Expression of vascular endothelial growth factor (VEGF) has been reported in renal cell carcinoma (RCC), a highly angiogenic carcinoma. However, little or no information is available on the expression of Ets-1, which is one of the target molecules of VEGF. In the present study, we examined the expression of Ets-1 and VEGF in RCC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), and correlations between expression and the microvessel density (MVD) were evaluated. Ets-1 was immunolocalized to carcinoma cells and endothelial cells of the microvessels in clear cell RCC, but not in papillary RCC. Immunohistochemical Ets-1 expression and MVD were significantly higher in clear cell RCC than in papillary RCC. Predominant mRNA expression of Ets-1 in clear cell RCC was confirmed by RT-PCR. The expression of Ets-1 correlated directly with MVD in clear cell RCC. Hypoxic treatment upregulated the mRNA expression of Ets-1 and VEGF in cell lines derived from clear cell RCC, suggesting that hypoxia is a key regulator for these molecules. These results demonstrate the expression of Ets-1 in human clear cell RCC and suggest the possibility that Ets-1 is involved in angiogenesis in clear cell RCC.</p>

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Assessment of long-term quality of life using the FACT-BL questionnaire in patients with an ileal conduit, continent reservoir, or orthotopic neobladder

Kikuchi Eiji, Horiguchi Yutaka, Nakashima Jun, Ohigashi Takashi, Oya Mototsugu, Nakagawa Ken, Miyajima Akira, Murai Masaru

Japanese Journal of Clinical Oncology 36 （ 11 ） 712 - 716 2006年09月

ISSN  0368-2811

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<p>Objective: To assess and compare quality of life (QOL) of patients followed for a long time who underwent an ileal conduit (IC), continent reservoir (CR) or ileal neobladder (NB) using FACT-BL, a bladder-cancer-specific questionnaire. Methods: One hundred and forty-seven patients underwent radical cystectomy and urinary diversion for bladder cancer from 1987 to 2002 at our institution. Of them, 79 (54%) patients were asked to participate in this study. Forty-nine patients (20 IC, 14 CR and 15 NB) returned the answered questionnaire for a survey response rate of 62%. Mean follow-up was 83.0 months. Results: Four categories (physical, social/familial, emotional and functional well-being) in FACT-G were equally favorable in these groups. Patients with IC had less trouble controlling urine but had a worse image on altered body appearance compared with NB patients. Interest in sex was extremely low in all patients and capability of maintaining an erection was also low in 39 male patients. The mean total value of FACT-BL in IC, CR and NB patients was 106.3 ± 16.4, 104.0 ± 14.2, and 110.9 ± 18.0, respectively, showing no significant difference. Ten (77%) of 13 IC, seven (78%) of nine CR and six (86%) of seven NB patients answered that they would choose the same type of diversion if they had the choice again. Conclusions: The type of urinary diversion does not appear to be associated with a different QOL by general cancer-related assessment. Urinary function and body image are affected and related to the method used to reconstruct the urinary system.</p>

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Usefulness of alpha₁-antichymotrypsin-PSA complex for predicting bone metastases of prostate cancer

Kikuchi Eiji, Nakashima Jun, Ishibashi Midori, Ohigashi Takashi, Oya Mototsugu, Nakagawa Ken, Miyajima Akira, Murai Masaru

Urology 68 （ 2 ） 371 - 375 2006年08月

ISSN  0090-4295

　概要を見る

<p>Objectives: To determine the usefulness of alpha₁-antichymotrypsin-prostate-specific antigen (PSA) complex (PSA-ACT)-based parameters in predicting bone metastasis in patients with prostate cancer. Methods: PSA-ACT, total PSA, free PSA, their volume-adjusted values, and alkaline phosphatase were evaluated in 220 consecutive patients with newly diagnosed prostate cancer. Results: Bone metastases were detected by bone scan in 27 (12.3%) of the 220 patients. The serum levels of PSA-ACT, total PSA, free PSA, PSA density, PSA adjusted for transition zone volume, PSA-ACT density, PSA-ACT adjusted for transition zone volume, alkaline phosphatase, PSA-ACT/PSA ratio, and Gleason score in patients with bone metastases were each significantly greater than in those without bone metastases. On receiver operating characteristic analyses, PSA-ACT had the greatest area under the curve (0.88), but the receiver operating characteristic curve demonstrated that the sensitivity and specificity of PSA-ACT were marginally better than those of total PSA at only a few selected cutoff points. At a sensitivity of 93% (2 patients with bone metastasis missed), unnecessary bone scans would have been avoided in 107 and 102 patients using a PSA-ACT cutoff value of 10 ng/mL and total PSA cutoff value of 11.5 ng/mL, respectively. Multivariate logistic regression analysis demonstrated that PSA-ACT and Gleason score were significant independent predictors of bone metastasis. Conclusions: PSA-ACT is as useful as total PSA for identifying patients with a low probability of having bone metastasis. PSA-ACT could replace PSA for predicting negative bone scans in a clinical setting in which PSA-ACT is used for monitoring and screening patients for prostate cancer.</p>

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Clinicopathological features predicting nodal metastasis of testicular seminoma

Sato Akinori, Ohigashi Takashi, Oya Mototsugu, Nakashima Jun, Marumo Ken, Murai Masaru

Urologia Internationalis 77 （ 1 ） 64 - 68 2006年07月

ISSN  0042-1138

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<p>Background/Aims: To investigate the clinical and pathological features which predict nodal metastasis and/or the prognosis of testicular seminoma and to evaluate the current treatment strategy in a single institute. Methods: We retrospectively analyzed 100 patients who had been pathologically diagnosed as having testicular seminoma in our institute. Ninety-one patients (91%) had stage I disease, 9 patients (9%) were stage II and none stage III. The median follow-up was 63.2 months (range 0.5-249). Results: The duration between the tumor recognition and the first outpatient visit ranged from 0 to 144 weeks, with a median of 5 weeks, which did not influence the clinical stage. The tumor diameter and the preoperative serum lactate dehydrogenase (LDH) level were the significant predictors of stage II disease. Following orchiectomy, 68 patients (74.7%) with stage I disease received radiotherapy. Only 1 patient who had not received adjuvant radiotherapy died from the recurrent disease. The 5-year survival was 100% for the irradiation group but 95% for the surveillance group, although the difference was not statistically significant. All the stage II patients were successfully treated with chemotherapy following orchiectomy. Conclusion: The maximum tumor diameter and the preoperative serum LDH level were the significant predictors of nodal metastasis. Adjuvant radiotherapy in patients with stage I seminoma did not influence the survival. Systemic chemotherapy promised good survival for the seminoma, even with nodal metastasis, in this series. Our results support the good prognosis of testicular seminoma with the current treatment strategy.</p>

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Treatment of renal cell carcinoma with interferons

Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 64 （ 7 ） 1281 - 1285 2006年07月

ISSN  0047-1852

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<p>Renal cell carcinoma (RCC) is considered to be an immunogenic cancer. RCC is refractory to chemotherapy and radiation. Immunotherapy including interferon (IFN)-alpha, gamma and interleukin-2 are the treatment of choice for metastatic RCC. IFN-alpha is most widely used in Japan. The response rate of IFN-alpha is 10-20 %. Lung lesions and lymphnodes are the usual effective sites. The survival benefit of IFN-alpha in patients with metastatic RCC has been shown in prospective randomized studies. Nephrectomy is recommended before interferon therapy if the patients have good performance status. Adjuvant interferon therapy failed to show any survival benefit after curative excision of primary RCC. The place of IFN-alpha is going to be changed due to the recent use of molecular targeting drugs.</p>

Maximum tumor diameter is a simple and valuable index associated with the local extent of disease in clinically localized prostate cancer

Mizuno Ryuichi, Nakashima Jun, Mukai Makio, Ookita Hajime, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

International Journal of Urology 13 （ 7 ） 951 - 955 2006年07月

ISSN  0919-8172

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<p>Background: The present study was undertaken to investigate the association of pathological features, including the total tumor volume (TTV), maximum tumor area (MTA), and maximum tumor diameter (MTD), with the local extent of disease in clinically localized prostate cancer. Methods: Serial whole sections of the prostate from 164 patients who underwent radical prostatectomy for localized prostate cancer were investigated. The correlations between the indicators of tumor size, including the TTV, MTA, and MTD, and other pathological parameters were evaluated. Results: The MTD, MTA, and TTV were significantly correlated with each other. Multivariate stepwise logistic regression analysis indicated that the Gleason score, perineural invasion, microvascular invasion, and MTD were significant independent parameters associated with extraprostatic disease. Conclusion: The histological tumor grade, perineural invasion, microvascular invasion, and tumor size were correlated with the local extent of disease. The MTD, a simple, easy, and inexpensive parameter, is a more significant pathological feature associated with the local extent of disease than the MTA or TTV.</p>

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Survivin associates with cell proliferation in renal cancer cells

Sato Akinori, Oya Mototsugu, Ito Keiichi, Mizuno Ryuichi, Horiguchi Yutaka, Umezawa Kazuo, Hayakawa Masamichi, Murai Masaru

International Journal of Oncology 28 （ 4 ） 841 - 846 2006年04月

ISSN  1019-6439

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<p>Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-κB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-γ. The combination of DHMEQ and IFN-γ inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivin-specific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-γ and/or an NF-κB inhibitor may therefore be a potential treatment modality for RCC.</p>

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-α and a novel NF-κB inhibitor

Akinori Sato, Mototsugu Oya, Keiichi Ito, Ryuichi Mizuno, Yutaka Horiguchi, kazuo Umezawa, Masamichi Hayakawa and Masaru Murai

International Jounrnal of Oncology 28   841+846 2006年03月

研究論文（学術雑誌）, 共著

腎細胞癌における分子異常

大家 基嗣

日本臨床 64 （ 増刊号2 ） 593-596 2006年02月

研究論文（学術雑誌）, 単著

Genetic backgrounds of renal cell carcinoma

Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 64 Suppl 2   593 - 596 2006年

ISSN  0047-1852

Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells

Mizuno Ryuichi, Oya Mototsugu, Hara Satoshi, Matsumoto Mayuko, Horiguchi Akio, Ohigashi Takashi, Marumo Ken, Murai Masaru

Oncology Reports 14 （ 3 ） 639 - 644 2005年09月

ISSN  1021-335X

　概要を見る

<p>Protein phosphatases have been classified into two basic types, namely protein serine/threonine phosphatase (PP), and protein tyrosine phosphatase (PTP). Cpd 5 is a selective inhibitor of cdc25 phosphatases, which belong to members of PTPs and regulate cell proliferation by controlling cyclin-dependent kinases (cdks). The present study was undertaken to investigate the potential utility of Cpd 5 as an anti-neoplastic agent for renal cell carcinomas (RCCs). Three renal cancer cell lines, 769P, Sw839, and A498 were used. The effects of Cpd 5 on the viability of renal cancer cell lines was analyzed using an Alamar Blue assay. Apoptosis was determined by flow cytometric TUNEL analysis. Changes in the expression of cdc25 phosphatases, mitogen-activated protein kinases (MAPKs), and bcl-2 family proteins were detected using Western blot analysis. The apoptosis-inducing effect of Cpd 5 on human RCC tissue was analyzed through TUNEL staining of organ cultures from RCCs. Cpd 5 showed a strong cytotoxicity against all renal cancer cell lines with an apoptosis-inducing effect. All cell lines treated with Cpd 5 resulted in a down-regulation of cdc25A, cdc25B, and cdc25C, however, the MAPK pathways were not affected. In addition, the up-regulation of bax, and the downregulation of bcl-2 and bcl-xL, was observed. In organ cultures from RCCs, TUNEL-positive apoptotic nuclei were observed when treated with Cpd 5. Cpd 5 was thus found to effectively inhibit the proliferation of human renal cancer cells while also inducing apoptosis by inhibiting cdc25 phosphatases and modulating bcl-2 family proteins. The administration of Cpd 5 may thus be an effective therapeutic approach for RCCs.</p>

c-Jun activation in acquired cystic kidney disease and renal cell carcinoma

Oya Mototsugu, Mikami Shuji, Mizuno Ryuichi, Marumo Ken, Mukai Makio, Murai Masaru

Journal of Urology 174 （ 2 ） 726 - 730 2005年08月

ISSN  0022-5347

　概要を見る

<p>Purpose: Activator protein-1 has a central role in transducing cytokine signals. Activator protein-1 is composed of 2 proto-oncogene families, namely Jun and Fos. Of them c-Jun has been suggested to have a role in cell cycle progression and neoplastic transformation. We examined the impact of c-Jun protein activation on pathological parameters in renal cell carcinoma (RCC). Materials and Methods: The expression of total c-Jun protein and phosphorylated c-Jun protein was determined by immunohistochemistry in 72 patients with RCC, including 10 with tumor arising from acquired cystic kidney disease (ACKD) of end stage kidneys. Results: c-Jun expression was observed in the distal but not the proximal tubules. Atypical hyperplastic cells in ACKD were positive for phosphorylated c-Jun. RCC arising in end stage kidneys was pT1 and 5 of these cases showed increased c-Jun activation. Of 62 cases arising from normally functioning kidneys 21 showed an increased degree of c-Jun activation. In localized small cell cases (pT1a) 55.5% (10 of 18) showed enhanced activation, whereas such enhanced activation was only observed in 25% (11 of 44) of more advanced cases (pT1b or greater). Therefore, c-Jun activation was considered to be related to the early carcinogenesis of RCC. Conclusions: This study emphasizes the role that c-Jun activation has in early RCC carcinogenesis. Thus, chronic stimulation of cytokines inducing c-Jun activation may have a role in the aberrant proliferation of hyperplastic atypical cells in ACKD and RCC.</p>

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Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alpha preparations

Oya Mototsugu, Asakura Hirotaka, Mizuno Ryuichi, Marumo Ken, Murai Masaru

Biomedical Research 26 （ 3 ） 135 - 137 2005年06月

ISSN  0388-6107

　概要を見る

<p>A 49-year-old man with pulmonary metastasis from renal cell carcinoma (RCC) was treated with recombinant IFN-α2b (Intron A®). A complete response was achieved within 4 months and thereafter persisted for 5 years until he developed another lung lesion. Interleukin-2 (Imunace®) was administered without any response. Finally, lie was treated by natural IFN-α (OIF®). The pulmonary lesion achieved a partial response after 11 months of treatment. Because IFN-α preparations include different subtypes, changing the use of IFN-α preparations may thus be a potentially useful option for the successful immunotherapy of RCC.</p>

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Akt activation in renal cell carcinoma

Hara S., Oya Moto, Mizuno R., Horiguchi A., Marumo K., Murai M.

Annals of Oncology 16 （ 6 ） 928 - 933 2005年06月

ISSN  0923-7534

　概要を見る

<p>Background: Akt has been implicated in the oncogenesis of human malignant tumors, because Akt regulates many key effector molecules involved in cell survival. PTEN (phosphatase and tensin homolog deleted on chromosome 10) negatively regulates Akt activation. Materials and methods: The expression of phosphorylated Akt (p-Akt), total Akt and PTEN was analyzed by Western blotting in 45 renal cell carcinoma (RCC) patients. The Bad and phosphorylated Bad (p-Bad) statuses were analyzed in 20 RCC patients. A phosphatidylinositol ether analog was used as an Akt inhibitor to treat four RCC cell lines, namely Caki-1, KU19-20, SW839 and Caki-2. Results: The PTEN expression in RCC was observed to decrease and p-Akt expression to increase significantly in comparison with that in the corresponding normal kidney tissue. The PTEN expression inversely correlated with the p-Akt expression. These alterations were specific for clear cell type RCC, but not for papillary or chromophobe type RCC. Alterations in Bad phosphorylation were also specifically observed in clear cell type. The Akt inhibitor induced apoptosis in KU19-20 and Caki-2 cells with a high Akt activity. Conclusions: A decreased expression of PTEN may be an underlying mechanism for Akt activation. An Akt inhibitor may be a therapeutic option for a subset of RCC with an elevated Akt activity.</p>

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New genetic causes of pheochromocytoma

Neumann Hartmut P H, Cybulla Markus, Shibata Hirotaka, Oya Mototsugu, Naruse Mitsuhide, Higashihara Eiji, Terachi Toshiro, Ling Hao, Takami Hiroshi, Shuin Taro, Murai Masaru

Keio Journal of Medicine 54 （ 1 ） 15 - 21 2005年03月

ISSN  0022-9717

　概要を見る

<p>Pheochromocytoma and paraganglioma are tumors of the autonomous nervous system mainly occurring in the adrenal medulla, but also in the extraadrenal paraganglias of the abdomen, thorax, neck and skull basis. The etiology comprises germline mutations of now 6 genes. About 10 years known are the RET gene susceptible for multiple endocrine neoplasia type 2, the VHL gene for von Hippel-Lindau Disease, and the NF 1 gene for neurofibromatosis Recklinghausen (neurofibromatosis type 1). Since 2000 the genes for succinatedehydrogenase subunits SDHB, SDHC, and SDHD have been identified for paraganglioma syndromes type 4, type 3, and type 1 respectively. Investigations of series of pheochromocytoma patients identified germline mutations in one of the genes SDHB, SDHD, VHL and RET in 24% to 50% of the patients. Multifocal tumors, young age and positive family history, known features associated with inheritence, have not been present in all patients. Therefore, analyses of blood DNA for mutations in these genes are recommended. Positive tests provide the patients and their relatives with essential platforms for clinical care. Experiences in this field of medicine have shown that optimal management of patients with pheochromocytoma-associated syndromes is a high challenge. National registries may be instrumental in order to provide with adequate facilities.</p>

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Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.

大家 基嗣

Ann Oncol 16   928-933 2005年

研究論文（学術雑誌）, 共著

Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alfa preparations.

大家 基嗣

Biomed Res 26   135-137 2005年

研究論文（学術雑誌）, 共著

C-jun activation in acquired cystic kidney disease and renal cell carcinoma.

大家 基嗣

J Urol 174   726-730 2005年

研究論文（学術雑誌）, 共著

Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells.

大家 基嗣

Oncol Rep 14   639-644 2005年

研究論文（学術雑誌）, 共著

血清PSAを用いた前立腺検診の検討

古平喜一郎, 中島淳, 宮嶋哲, 堀口裕, 中川健, 大家基嗣, 大東貴志, 柴田洋孝, 齋藤郁夫, 村井勝

泌尿器外科 18 （ 8 ） 1017-1019 2005年

研究論文（学術雑誌）, 共著