論文 - 大家　基嗣

Detection of Circulating Prostate Cells during Radical Prostatectomy by Standardized PSMA RT-PCR

Schmidt Bettina, Anastasiadis Aristotelis G., Seifert Hans Helge, Franke Knut H., Oya Mototsugu, Ackermann Rolf

Anticancer Research 23 （ 5 A ） 3991 - 3999 2003年09月

ISSN  0250-7005

　概要を見る

<p>Background: The purpose of this study was to establish a quantitative standardized RT-PCR for the detection of Prostate Specific Membrane Antigen (PSMA)-expressing circulating cells and to evaluate clinical relevance in patients undergoing radical retropubic prostatectomy (RRP) for clinically localized prostate cancer (PCa). Materials and Methods: An external standard molecule (PSMA MIMIC) was constructed for standardization of PSMA RT-PCR reactions. It has the same sequence as endogenous PSMA, except for a central 85 bp deletion, allowing the amplification of both targets simultaneously with nearly the same amplification characteristics as in a nested PCR. PSMA RT-PCR was performed from peripheral blood samples of 73 patients with clinically localized PCa, 4 with metastatic PCa, 27 with benign prostatic hyperplasia (BPH) and 27 controls. Pre, intra- and postoperative blood samples were tested for circulating PSMA expressing cells in 54 out of 73 patients with clinically localized PCa. We also tested intraoperative blood samples of 19 BPH patients treated by transurethral or open surgery. Results: Endogenous PSMA signals from PCa patients varied between 850 and 9900 transcript molecules, corresponding to 2-20 PSMA-expressing cells/ml blood. Standardized RT-PCR using the PSMA MIMIC molecule revealed a significant decrease of "false-positives" in cancer-free controls (p=0.004). Controls could clearly be distinguished from prostate cancer patients based on PSMA PCR positivity (p=0.003). Thirty-two % of patients with localized prostate cancer, 11% of BPH patients and 7% of healthy controls were positive in standardized assays compared to 48%, 30% and 27% without PSMA MIMIC, respectively. Preoperatively, a correlation with tumor stage (p=0.030), grade (p=0.035) and Gleason Score (p=0.03) could be demonstrated in clinically localized PCa patients. Dissemination of prostate cells during surgery occurred in 32% of the RRPs and 21% of BPH patients. Positive PCR signals from intraoperative blood samples correlated with positive lymph node status (p=0.007) and tumor grade (p=0.005). Postoperative positive results correlated with grade (p=0.012) and Gleason Score (p=0.035). Conclusion: Counseling the patient with clinically localized prostate cancer can be challenging. Surgery may be, in retrospect, inappropriate in a number of patients due to preoperative understaging. This newly constructed external standard allows quantitative detection of circulating prostate cells, and therefore may open new perspectives for PSMA RT-PCR techniques as diagnostic assays and tools for post-therapeutic follow-up.</p>

Prediction of extraprostatic cancer by prostate specific antigen density, endorectal MRI, and biopsy gleason score in clinically localized prostate cancer

Horiguchi Akio, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Prostate 56 （ 1 ） 23 - 29 2003年06月

ISSN  0270-4137

　概要を見る

<p>BACKGROUNDS. The present study was designed to identify the preoperative parameters, including PSA-based parameters, and endorectal MRI, predictive of pathological stage in males who underwent radical prostatectomy. METHODS. We studied 114 patients who underwent radical retropubic prostatectomy and pelvic lymphadenectomy for clinically localized prostate cancer. Clinical stage was assessed by DRE, pelvic CT scan, endorectal MRI, and bone scan. The correlation between the preoperative parameters, including PSA-based parameters, clinical stage, and histological findings of biopsy specimens, and the pathological stage was analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for local extent of disease. RESULTS. Seventy-six (66.6%) patients had organ confined cancer and 38 (33.4%) patients had extraprostatic cancer. Of the 38 patients with extraprostatic cancer, four had seminal vesicle involvement, while, none had pelvic lymph node involvement. Biopsy Gleason score, PSA, PSA-α1-antichymotrypsin (PSA-ACT), PSA-density (PSAD), PSA-transition zone density, PSA-ACT density, and PSA-ACT transition zone (TZ) density were significantly higher and percent free PSA was lower in the patients with organ confined cancer than those with extraprostatic cancer (P &lt; 0.01). PSAD showed the largest area under the ROC curve (AUC) among those parameters (AUC = 0.732). Sixty-eight (74.7%) of 91 patients with T2 on endorectal MRI had organ confined cancer, while 15 (65.2%) of 23 patients with T3 had extraprostatic cancer (P &lt; 0.01). Multivariate logistic regression analysis indicated that Gleason score (≥7 vs. ≤6), endorectal MRI findings, and PSAD were significant predictors of extraprostatic cancer (P &lt; 0.01). CONCLUSIONS. The present study demonstrated that preoperative PSAD was the most valuable predictor among PSA-based parameters for extraprostatic disease in patients with clinically localized prostate cancer. The combination of PSAD, endorectal MRI findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.</p>

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'Prediction of extraprostatic cancer by prostate specific antigen density, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer'

'Horiguchi Akio, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken and Murai Masaru'

Prostate 56 （ 1 ） 23-29 2003年06月

研究論文（学術雑誌）, 共著

Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma

Oya Mototsugu, Takayanagi Atsushi, Horiguchi Akio, Mizuno Ryuichi, Ohtsubo Masafumi, Marumo Ken, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 24 （ 3 ） 377 - 384 2003年03月

ISSN  0143-3334

　概要を見る

<p>Although an aggressive phenotype of renal cell carcinoma (RCC) is known to frequently be associated with inflammatory paraneoplastic syndrome including serum C-reactive protein (CRP) elevation, the molecular mechanism underlying this clinical phenomenon as well as what yields the malignant phenotype leading to the progression of RCC has yet to be elucidated. Based on the increased level of inflammatory cytokines such as interleukin-6 in advanced cases of RCC, a cytokine-inducible transcription factor, namely, nuclear factor-κB (NF-κB), may thus play a role in the progression of RCC. An electrophoretic mobility shift assay (EMSA) was carried out to determine the activity of NF-κB. Out of 45 cases of RCC, 15 cases (33%) showed a &gt;200% increase in the NF-κB activity in comparison with that seen in normal renal tissue. In locally advanced cases (≥pT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (≤pT2). All three cases with metastases showed an increased NF-κB activity. The NF-κB activity determined by EMSA was further confirmed by an immunohistochemical analysis using an antibody recognizing the nuclear localization signal (NLS) in p65 subunit of NF-κB. The serum CRP elevation correlated with the increased NF-κB activation, and therefore NF-κB may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-κB activity was associated with an increased expression of both the p65 and p50 subunits of NF-κB and a concomitant decreased expression of IκBα. No functional mutations of the IκBα gene were detected. The NF-κB activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.</p>

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Increased activation of CCAAT/enhancer binding protein-β correlates with the invasiveness of renal cell carcinoma

Oya Mototsugu, Horiguchi Akio, Mizuno Ryuichi, Marumo Ken, Murai Masaru

Clinical Cancer Research 9 （ 3 ） 1021 - 1027 2003年03月

ISSN  1078-0432

　概要を見る

<p>Positive inflammatory reactions in an aggressive phenotype are typical features of renal cell carcinoma (RCC). Although a high blood level of inflammatory cytokines, such as interleukin-6, interleukin-8, and tumor necrosis factor-α, has been observed in these patients, the mechanisms underlying this clinical phenomenon remain to be elucidated. CCAAT/enhancer binding protein (C/EBP) family are transcription factors which play a role in cell differentiation and inflammatory reactions. Among these, C/EBP-β induces a variety of cytokines and thus may play a role in the pathogenesis of RCC. We studied the activation of C/EBP-β determined by electrophoretic mobility shift assay in nine RCC cell lines and 44 tissue samples. Six cell lines showed an activation of C/EBP-β, whereas three cell lines did not, and two of these three had no expression at all of C/EBP-β protein. Of 44 tissue samples, 12 (27.3%) showed a &gt;200% increase in the activity compared with the corresponding normal kidney tissues. Locally advanced cases had a significantly higher rate of increased C/EBP-β activity (5 of 8 = 62.5% in advanced cases versus 7 of 36 = 19.4% in localized cases). Especially, all four cases with renal vein invasion had an increased C/EBP-β activity. These data suggest that the increased activation of C/EBP-β may contribute to promote tumor invasiveness and render a malignant phenotype of RCC, although it needs to be validated in a larger series.</p>

Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma

Oya Mototsugu, Takayanagi Atsushi, Horiguchi Akio, Mizuno Ryuichi, Ohtsubo Masafumi, Marumo Ken, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 24 （ 3 ） 377-384 2003年03月

研究論文（学術雑誌）, 共著

Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma

Horiguchi Akio, Oya Mototsugu, Uchida Atsushi, Marumo Ken, Murai Masaru

Journal of Urology 169 （ 2 ） 710 - 713 2003年02月

ISSN  0022-5347

　概要を見る

<p>Purpose: Akt has been implicated in the pathogenesis and progression of numerous human malignant tumors because Akt regulates many key effector molecules involved in controlling the balance of survival and apoptosis. Elevated Akt activation has been demonstrated in various types of malignant tumors. In the current study we evaluated Akt activation in renal cell carcinoma and investigated its association with pathological features and clinical outcome. Materials and Methods: Akt activation was evaluated by immunohistochemistry using antiphospho-specific Akt antibody, which recognizes only activated Akt, in 48 patients with renal cell carcinoma. High immunostaining tumors were defined as tumors with increased staining intensity compared with adjacent nonneoplastic kidney tissue and low immunostaining tumors were defined as tumors with equivalent or decreased staining intensity. The association of Akt activation status with clinicopathological features was analyzed. Results: Of 48 patients examined 18 (37.5%) demonstrated high antiphospho-specific Akt immunostaining compared with adjacent nonneoplastic kidney tissue, while 30 (62.5%) demonstrated low immunostaining. Elevated immunostaining was significantly associated with tumor grade (p = 0.0354) and metastatic disease (p = 0.0044), while it was not associated with tumor stage or histological subtype. In addition, high antiphospho-specific Akt immunostaining was significantly associated with a poor cancer specific survival rate on univariate analysis (p = 0.0109) but not on multivariate analysis. Conclusions: Elevated Akt activation could be a common finding, especially in high grade tumor and metastatic disease. It could have an important role in the pathogenesis and progression of renal cell carcinoma.</p>

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Enhancement of diethylstilbestrol induced cytotoxicity by Bcl-2 antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer

Kikuchi Eiji, Nakashima Jun, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Journal of Urology 169 （ 2 ） 730 - 734 2003年02月

ISSN  0022-5347

　概要を見る

<p>Purpose: Bcl-2 has been shown to prolong cancer cell survival by blocking apoptosis and have the function of scavenging reactive oxygen species. We assessed the efficacy of a novel strategy that relies on antisense bcl-2 oligodeoxynucleotides as well as a glutathione depletor combined with diethylstilbestrol (DES) for hormone independent prostate cancer. Materials and Methods: The cytotoxic effects of antisense bcl-2 oligodeoxynucleotides and DES on PC-3 cells were determined using spectrophotometry measurement. The expression of Bcl-2 protein was detected by Western blot analysis. Intracellular reactive oxygen species generation was estimated from the amount of intracellular dichlorofluorescein. Apoptosis was determined by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling assay. Results: Antisense bcl-2 oligodeoxynucleotides decreased Bcl-2 protein levels and significantly inhibited PC-3 cell growth in a dose dependent manner. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity. A significant increase in apoptotic cells was induced by the combination of antisense bcl-2 oligodeoxynucleotides and DES compared with the oligodeoxynucleotides alone. The glutathione depletor buthionine sulfoximine significantly decreased the intracellular concentration of glutathione and augmented DES induced cytotoxicity and reactive oxygen species generation in PC-3 cells. Neither the generation of reactive oxygen species nor the intracellular concentration of glutathione was influenced by antisense bcl-2 oligodeoxynucleotide treatment. Conclusions: Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells through the apoptotic pathway independent of augmented reactive oxygen species generation, whereas the glutathione depletor augmented cytotoxicity and reactive oxygen species generation.</p>

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Incidence and growth pattern of simple cysts of the kidney in patients with asymptomatic microscopic hematuria

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Nakashima Jun, Murai Masaru

International Journal of Urology 10 （ 2 ） 63 - 67 2003年02月

ISSN  0919-8172

　概要を見る

<p>Background: We examined the incidence and natural history of simple renal cysts found by ultrasonography (US) in patients referred for asymptomatic microscopic hematuria. Methods: Among the 906 patients aged 18-78 years, 743 patients who had undergone US were included in the present study. The natural history of simple renal cysts was investigated in 55 patients who underwent periodical US examinations for more than 3 years. Results: The incidence of simple renal cysts was 4.3% for ages 29 years or younger, 15.3% for ages 30-39, 21.8% for ages 40-49, 23.3% for ages 50-59 and 32.6% for ages 60 years or older; thus the incidence increased in older age groups (P = 0.0005 for men, P = 0.0020 for women). Men tended to have a higher incidence than women. The degree of hematuria did not influence the incidence of renal cysts (P = 0.9044). The annual growth rate of the mean maximum diameter was 4.2% during a 3-year follow-up period in 55 patients and 5.1% during a 6-year follow-up in 31 patients. Conclusion: Since the diameter of a renal cyst may increase by 5% annually, the diameter of the cyst may increase by 1.6 times in 10 years. The scheduling of follow-up examinations depends on the size at the time of disclosure, the effects on calyceal systems, or the suspicion of a concurrent malignant disease. However, the most simple renal cysts may be followed-up at an interval of more than 10 years, once a diagnosis has been established.</p>

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Incidence and growth pattern of simple cysts of the kidney in patients with asymptomatic microscopic hematuria

'Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Nakashima Jun and Murai Masaru.'

International Journal of Urology 10 （ 2 ） 63-67 2003年02月

研究論文（学術雑誌）, 共著

Suppression of hormone-refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice

Kikuchi Eiji, Horiguchi Yutaka, Nakashima Jun, Kuroda Kenji, Oya Mototsugu, Ohigashi Takashi, Takahashi Nozomu, Shima Yutaka, Umezawa Kazuo, Murai Masaru

Cancer Research 63 （ 1 ） 107 - 110 2003年01月

ISSN  0008-5472

　概要を見る

<p>We have synthesized and explored the feasibility of using a novel nuclear factor (NF) κB inhibitor, a dehydroxymethylepoxyquinomicin designated as DHMEQ, against prostate cancer. The activity of NFκB, evaluated by transient transfection of a luciferase reporter DNA containing a specific binding sequence for NFκB, was inhibited by DHMEQ in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3. Statistically significant growth inhibition was achieved by 20 μg/ml of DHMEQ, and marked levels of apoptosis were induced 48 h after DHMEQ administration in vitro. Electrophoretic mobility shift assay showed that DHMEQ completely inhibited NFκB DNA binding activity in JCA-1 cells. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude mice without any side effects. Our result indicates the possibility of using a novel NFκB activation inhibitor, DHMEQ, as a new treatment strategy against hormone-refractory prostate cancer.</p>

Suppresion of Hormone-refractory Prostate Cancer by a Novel Nuclear Factor kB Inhibitor in Nude Mice

菊地 栄次

Cancer Research 63   107-110 2003年01月

研究論文（学術雑誌）, 共著

A case of renal cell carcinoma associated with renal tubulopapillary adenoma in hemodialysis patient

Ebine Takashi, Nakagawa Ken, Oya Mototsugu, Murai Masaru, Mukai Makio

Japanese Journal of Clinical Urology 57 （ 10 ） 839 - 841 2003年

ISSN  0385-2393

　概要を見る

<p>A 67-year-old male with chronic renal failure had been on a hemodialysis treatment for 3 years and 4 months. He presented with a left renal mass incidentally detected on abdominal ultrasound examination. The T2-weighted MRI demonstrated a hyperintense mass at the lower pole and a hypointense mass at the upper pole respectively. They were diagnosed as renal cell carcinomas and left radical nephrectomy was performed. Histopathological diagnoses of the specimen were renal cell carcinoma and renal tubulopapillary adenoma respectively.</p>

振動装置付き陰茎締め付けバンドの評価

丸茂健、　堀口裕、　中川健、　大家基嗣、　大東貴志、　中島　淳、　村井勝

日本性機能学会雑誌 18 （ 1 ） 39087 2003年

研究論文（学術雑誌）, 共著

Renal cell carcinoma: relevance of pathology

'Mototsugu Oya, Murai Masaru'

Current Opinion in Uroloyg 13   445-449 2003年

研究論文（学術雑誌）, 共著

Detection of Circulating Prostate Cells during Radical Prostatectomy by Standardized PSMA RT-PCR: Association with Positive Lymph Nodes and High Malignant Grade

'Bettina Schmidt, Aristotelis G. Anastasiadis, Hans-Helge Seifert, Knut H. Franke,Mototsugu Oya and Rolf Ackermann'

Anticancer Research 23   3991-4000 2003年

研究論文（学術雑誌）, 共著

高プロラクチン血症を有する勃起障害患者の検討

丸茂健、　宮嶋哲、　堀口裕、　中川健、　大家基嗣、　大東貴志、　中島淳、　村井勝

日本性機能学会雑誌 18 （ 3 ） 313-317 2003年

研究論文（学術雑誌）, 共著

透析腎に発生した乳糖状腺腫を伴う腎細胞癌

海老根崇、中川健、大家基嗣、村井勝、向井万起男

臨床泌尿器科 57   839-841 2003年

研究論文（学術雑誌）, 共著

経皮的膀胱癌穿刺とcystostomy

大家 基嗣, 村井　勝

消化器外科  （ 26 ） 921-927 2003年

研究論文（学術雑誌）, 単著

腎細胞癌におけるアポトーシスの誘導ーTRAILの抗腫瘍効果とNFκBを標的とした遺伝子治療を中心にー

大家 基嗣

泌尿器科外科  （ 16 ） 1089-1091 2003年

研究論文（学術雑誌）, 単著