研究者詳細 - 大家　基嗣

論文 - 大家　基嗣

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New genetic causes of pheochromocytoma: current concepts and the clinical relevance.

大家基嗣

Keio J Med, 54 15-21 2005年

研究論文（学術雑誌）, 共著

Three-dimensional ultrasonography in evaluation of benign prostatic hyperplasia

Kanao Kent, Kikuchi Eiji, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

International Journal of Urology 11 （ 12 ） 1087 - 1091 2004年12月

ISSN 0919-8172

Background: The clinical application of volume estimation by 3-D ultrasound has recently gained much attention. However, there have been no reports evaluating the prostate volume by 3-D transrectal ultrasound (TRUS) before transurethral resection of the prostate (TURP). The purpose of the present study was to evaluate the value of 3-D TRUS for prediction of prostate morphology and resected weight before TURP and to investigate whether 3-D TRUS is a more useful examination than 2D TRUS in patients with benign prostatic hyperplasia (BPH). Methods: Transurethral resection of the prostate was performed in 23 patients with BPH. We evaluated the prostate morphology and measured both the volumes of the whole prostate and the transition zone using 2-D and 3-D TRUS, respectively. The actual resected weight was recorded and compared with the volume of the whole prostate and that of the transition zone measured by 2D and 3-D TRUS. Results: The volume of the transition zone measured by 3-D TRUS correlated most strongly with the resected weight (r = 0.84). A large median lobe was seen in three patients in whom the transition zone volume measured by 2-D TRUS was considerably larger than the resected weight. However, overestimation in the three patients decreased by the use of 3-D TRUS. Conclusions: It was concluded that 3-D TRUS was equal or superior to 2-D TRUS in prediction of the resected weight and 3-D TRUS offers better information as a diagnostic tool before TURP.

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Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells.

Ishizawa J., Yoshida Shuichi, Oya Mototsugu, Mizuno Ryuichi, Shinojima Toshiaki, Marumo Ken, Murai Masaru

International Journal of Oncology 25 （ 3 ） 697 - 702 2004年09月

ISSN 1019-6439

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.

Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells

Mizuno Ryuichi, Oya Mototsugu, Shiomi Takayuki, Marumo Ken, Okada Yasunori, Murai Masaru

Journal of Urology 172 （ 2 ） 723 - 727 2004年08月

ISSN 0022-5347

Purpose: Mitogen-activated protein kinases (MAPKs) comprise 3 subgroups, that is extracellular signal-regulated protein kinase, c-Jun N-terminal kinase (JNK) and p38 MAPK (p38). In this study we analyzed the role of JNK as well as the expression of MAPK phosphatase-1 (MKP-1) in renal cancers. Materials and Methods: Four renal cell carcinoma (RCC) cell lines were used. The effects of anisomycin (JNK activator) and Ro-318220 (MKP-1 expression inhibitor) were analyzed by alamar blue assay. Apoptosis was determined by flow cytometric TUNEL analysis, nuclear morphological alternations and the detection of DNA fragmentation. Changes in MKP-1 expression as well as the activation of extracellular signal-regulated protein kinases and JNK were analyzed by Western blotting. Results: All cell lines treated with anisomycin resulted in a transient activation of JNK without inducing apoptosis. Since we hypothesized that elevated MKP-1 expression could possibly prevent persistent JNK activation, Ro-318220 was used. When cells were treated with Ro-318220, MKP-1 expression decreased in Caki-1 and KU 20-01 cells but not in ACHN or 769P cells. Combined treatment of Caki-1 and KU 20-01 cells with anisomycin and Ro-318220 resulted in a decrease in MKP-1 expression concomitant with persistent JNK activation. Apoptosis was induced in each cell line. Conclusions: These results suggest that prevalent MKP-1 expression in RCC contributes to cancer cell survival by attenuating an apoptosis inducing signal cascade via JNK. Since Ro-318220 potentiated JNK related apoptosis, JNK activation by blocking MKP-1 expression may be an effective therapeutic approach to RCC.

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Dexamethasone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome

Shinojima Toshiaki, Oya Mototsugu, Kohno Hidaka, Marumo Ken, Murai Masaru

International Journal of Urology 11 （ 7 ） 553 - 556 2004年07月

ISSN 0919-8172

Interleukin-2 (IL-2) in combination with dexamethasone was administered to a 48-year-old man with renal cell carcinoma accompanied by paraneoplastic inflammatory syndrome, including progressive multiple lung metastases and inferior vena caval tumor thrombus. Although non-steroidal anti-inflammatory drugs had no apparent antipyretic effect on the systemic inflammatory syndrome, oral administration of dexamethasone achieved complete antipyresis and improved his quality of life. After a 4-week period of IL-2 treatment, regression of metastasized lesions was demonstrated despite concurrent oral administration of dexamethasone. Steroids might reduce the action of immunotherapeutic drugs, but in some cases, combination therapy can achieve both alleviation of the paraneoplastic syndrome and tumor shrinkage.

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Differential expression of activator protein-2 isoforms in renal cell carcinoma

Oya Mototsugu, Mikami Shuji, Mizuno Ryuichi, Miyajima Akira, Horiguchi Yutaka, Nakashima Jun, Marumo Ken, Mukai Makio, Murai Masaru

Urology 64 （ 1 ） 162 - 167 2004年07月

ISSN 0090-4295

Objectives To investigate the expression of activator protein-2 (AP-2) in renal cell carcinoma (RCC) by immunohistochemistry. Three AP-2 isoforms alpha (α), beta (β), and gamma (γ) are known to exhibit a highly homologous structure; however, their functions are considered to be different. AP-2 has been implicated to play a role in carcinogenesis, as well as in the development of the kidney. Methods The expression of the three AP-2 isoforms, α, β, and γ, was determined in 58 patients with RCC by immunohistochemistry. Epidermal growth factor receptor and erbB2 expression in 42 patients with RCC was also evaluated to investigate the correlation with AP-2 isoforms. Results AP-2 isoforms are differentially expressed in normal renal tubules. Of 58 RCC tissue specimens, 15 (25.9%) demonstrated nuclear and cytoplasmic expression of AP-2α. Clear cell RCC had a significantly greater rate of AP-2α expression than the nonclear subtypes (14 of 41 clear versus 1 of 17 nonclear subtypes). Of the 58 specimens, 8 (13.8%) showed nuclear staining for AP-2β; notably, localized small cases had a significantly greater rate of nuclear staining for AP-2β (5 of 13 in pT1a versus 3 of 45 in pT1b or greater). In addition, only 2 cases (3.5%) demonstrated nuclear staining for AP-2γ. Epidermal growth factor receptor and erbB2 expression did not correlate with expression of the AP-2 isoforms. Conclusions AP-2 isoforms were differentially expressed in RCC, as well as in the adult normal kidney. AP-2α was dominantly expressed in clear cell RCC. AP-2β expression was observed in the low-stage subtypes of RCC, and this transcription factor may be related to early carcinogenesis.

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Renal cell carcinoma

Murai Masaru, Oya Mototsugu

Current Opinion in Urology 14 （ 4 ） 229 - 233 2004年07月

ISSN 0963-0643

Purpose of review: The incidence of renal cell carcinoma has been increasing worldwide. Although the etiology of renal cell carcinoma is largely unknown, recent epidemiological investigations have shed some light on the issue. This article reviews the literature related to etiology, incidence and epidemiology of renal cell carcinoma published between May 1, 2003 and April 30, 2004. Recent findings: Accumulating evidence has confirmed the increasing incidence of renal cell carcinoma. A racial disparity has been reported for the first time. Being overweight and obesity were confirmed to be risk factors for renal cell carcinoma. Recreational exercise was shown to reduce the risk, whereas a Western-style diet and smoking increased the risk. Occupational exposure may relate to the development of renal cell carcinoma; however, no definite carcinogens have so far been identified. A susceptibility to develop renal cell carcinoma may also exist in relation to the gene polymorphisms of detoxifying enzymes including glutathione S-transferase and cytochrome P450. Summary: Although high-risk groups for renal cell carcinoma have been identified, a large portion of renal cell carcinoma still has an unknown etiology. Life-style modifications might reduce renal cell carcinoma risks. Further studies are thus needed to explore the etiology of renal cell carcinoma in terms of gene-environment interactions.

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Endorectal MRI for prediction of tumor site, tumor size, and local extension of prostate cancer

Nakashima Jun, Tanimoto Akihiro, Imai Yutaka, Mukai Makio, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Urology 64 （ 1 ） 101 - 105 2004年07月

ISSN 0090-4295

Objectives To assess the value of endorectal magnetic resonance imaging (MRI) for detecting the tumor site, tumor size, and disease extent in patients with localized prostate cancer. Methods The MRI findings were compared with the histopathologic findings of radical prostatectomy specimens in 95 patients. Results The histologic examination revealed 186 cancer foci. Endorectal MRI detected 109 cancer foci. The accuracy, sensitivity, and positive predictive value of endorectal MRI for detecting tumor foci greater than 1.0 cm in diameter was 79.8%, 85.3%, and 92.6%, respectively; the corresponding value for detecting tumor foci smaller than 1.0 cm was 24.2%, 26.2%, and 75.9%, respectively. The maximal tumor diameter on endorectal MRI correlated with that shown by histologic examination for tumors larger than 1.0 cm in diameter. However, it did not correlate significantly with the histologic diameter of tumors smaller than 1.0 cm. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of endorectal MRI was 74.7%, 57.1%, 82.1%, 57.1%, and 82.1%, respectively, for the detection of extracapsular extension and was 75.8%, 62.1%, 81.8%, 60.0%, and 83.1%, respectively, for local staging. Conclusions The results of the present study suggest that endorectal MRI is useful for predicting local extension, as well as tumor site and tumor size, of cancer foci greater than 1.0 cm in diameter.

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The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors

Ito Keiichi, Nakashima Jun, Hanawa Yasumasa, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Journal of Urology 171 （ 1 ） 120 - 125 2004年01月

ISSN 0022-5347

Purpose: Since middle-aged and elderly patients seem to have risk factors affecting renal function, it is important to predict postoperative renal function prior to unilateral nephrectomy (UNx). We evaluated preoperative factors for predicting postoperative renal function in middle-aged and elderly patients with renal cell carcinoma (RCC) treated with radical nephrectomy (RNx). Materials and Methods: In 201 patients who underwent RNx preoperative records and postoperative serum creatinine (SCR) 6 years after nephrectomy were available. Postoperative renal insufficiency was defined as serum creatinine 1. 4 mg/dl or greater. The relationship of each preoperative and postoperative factor was analyzed. Logistic regression analysis was performed to evaluate preoperative factors for predicting postoperative SCR 1.4 mg/dl or greater after 6 years. Results: There was a significant difference in postoperative SCR between female and male patients, and between those with and without hypertension, diabetes and proteinuria (p <0.05). Age, hemoglobin, preoperative SCR, blood urea nitrogen, uric acid and K significantly correlated with postoperative SCR (p <0.05). The increase in SCR during 6 years after UNx was significantly higher in patients with hypertension, diabetes and proteinuria than in their respective counterparts (p <0.05). Multivariate stepwise logistic regression analysis demonstrated that preoperative serum creatinine, hypertension and proteinuria were significant independent factors predicting postoperative renal function 6 years after UNx in patients with RCC (p <0.05). Conclusions: Preoperative SCR, hypertension and proteinuria are useful factors for predicting postoperative renal function after RNx in patients with RCC.

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The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors

'Ito Keiichi, Nakashima Jun, Hanawa Yasumasa, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru'

Journal of Urology 171 120-125 2004年01月

研究論文（学術雑誌）, 共著

Dexamethazone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome.

大家基嗣

Int J Urol., 11 553-556 2004年

研究論文（学術雑誌）, 共著

内分泌治療を受けている前立腺癌患者の骨粗鬆症診断の意義

'丸茂健,　堀口裕,　中川健,　大家基嗣,　大東貴志,　中島淳,　村井勝'

腎泌尿器予防医学会雑誌 12 （ 1 ） 62-66 2004年

研究論文（学術雑誌）, 共著

Endorectal MRI for prediction of tumor site, tumor size, and local extension of prostate cancer

Jun Nakashima, Akihiro Tanimoto, Yutaka Imai, Makio Mukai, Yutaka Horiguchi, Ken Nakagawa, Mototsugu Oya, Takashi Ohigashi, Ken Marumo, Masaru Murai

Urology 64 101-105 2004年

研究論文（学術雑誌）, 共著

Three-dimensional ultrasonography in evaluation of benign prostatic hyperplasia.

金尾健人

Int J Urol 11 1087-1091 2004年

研究論文（学術雑誌）, 共著

内分泌療法が施行された進行性前立腺癌におけるＣ反応性蛋白の意義

中島淳、宮嶋哲、堀口裕、中川健、大家基嗣、大東貴志、丸茂健、村井勝

泌尿器外科 17 951-954 2004年

研究論文（学術雑誌）, 共著

Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells.

大家基嗣

J. Urol., 172 723-727 2004年

研究論文（学術雑誌）, 共著

Differential expression of activator protein-2 isoforms in renal cell carcinoma.

大家基嗣

Urology, 64 162-167 2004年

研究論文（学術雑誌）, 共著

Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induce apoptosis in renal cancer cells.

大家基嗣

Int J Oncol., 25 697-702 2004年

研究論文（学術雑誌）, 共著

Renal cell carcinoma: etiology, incidence and epidemiology.

大家基嗣

Curr Opin Urol, 14 229-233 2004年

研究論文（学術雑誌）, 共著

Renal cell carcinoma

Oya Mototsugu, Murai Masaru

Current Opinion in Urology 13 （ 6 ） 445 - 449 2003年11月

ISSN 0963-0643

Purpose of review: Although pathological findings including tumour grade and tumour-node-metastasis stage provide prognostic information, the outcome for patients with renal cell carcinoma is occasionally unpredictable. Many studies have been undertaken to improve prediction of the prognosis of renal cell carcinoma, along with efforts to clarify the pathogenesis of renal cell carcinoma at the molecular level. This article reviews the advances in renal cell carcinoma research relevant to pathology published between 1 May 2002 and 30 April 2003. Recent findings: The establishment of a strict tumour grading system or adding microscopic venous invasion or tumour necrosis is potentially useful for predicting patient outcomes. The contribution of the von Hippel-Lindau-related pathway in early carcinogenesis has been partly revealed with regard to angiogenesis and cell cycle control. Tumour development in renal cell carcinoma can be considered as accumulating heterogenous molecular events related to cytokine production, cell cycle control, anti-apoptotic signal machinery and angiogenesis. Summary: Finding the target genes related to the von Hippel-Lindau pathway may explain the resistance of chemotherapy, and also provide a clue to finding a novel therapeutic option. Molecular targeting therapy can be applicable after more general molecules leading to tumour development and the metastasis of renal cell carcinoma have been identified.

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