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| 1.
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Konaka, Hiroyuki ; Egawa, Shin ; Saito, Shiro ; Yorozu, Atsunori ; Takahashi, Hiroyuki ; Miyakoda, Keiko ; Fukushima, Masanori ; Dokiya, Takushi ; Yamanaka, Hidetoshi ; Stone, Nelson N. ; Namiki, Mikio ; 小中, 弘之 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Background: Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and ad
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vanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.Methods/Design: This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 ( 125I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with 125I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during 125I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.Discussion: To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.Trial registration: UMIN000003992. © 2012 Konaka et al; licensee BioMed Central Ltd.
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| 2.
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Namiki, Mikio ; Kitagawa, Yasuhide ; Mizokami, Atsushi ; Koh, Eitetsu
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金沢大学医薬保健研究域医学系<br />Background: The basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT
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), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT. Methods: A retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out. Results: It was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation. Conclusion: Algorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated. © 2008 WPMH GmbH.
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| 3.
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Arakawa, Hiroshi ; Nakanishi, Takeo ; Yanagihara, Chihiro ; Nishimoto, Tomohiro ; Wakayama, Tomohiko ; Mizokami, Atsushi ; Kawai, Keiichi ; Tamai, Ikumi
概要:
The biological mechanisms underlying castration resistance of prostate cancer are not fully understood. In the present s
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tudy, we examined the role of organic anion transporting polypeptides (OATPs) as importers of dehydroepiandrosterone sulfate (DHEAS) into cells to support growth under androgen-depleted conditions. Cell growth and mRNA expression of OATP genes were studied in human prostate cancer LNCaP and 22Rv1 cells under androgen-depleted conditions. The stimulatory effect of DHEAS on cell growth was investigated in LNCaP cells in which OATP1A2 had been silenced. Growth of both cell lines was stimulated by DHEAS and the effect was attenuated by STX64, an inhibitor of steroid sulfatase which can covert DHEAS to DHEA. OATP1A2 mRNA expression was increased most prominently among various genes tested in LNCaP cells grown in androgen-depleted medium. Similar results were obtained with 22Rv1 cells. Furthermore, the characteristics of [ 3H]DHEAS uptake by LNCaP cells were consistent with those of OATP-mediated transport. Knockdown of OATP1A2 in LNCaP cells resulted in loss of the DHEAS sensitivity of cell growth. Our results suggest that enhanced OATP1A2 expression is associated with adaptive cell growth of prostate cancer cells under androgen-depleted conditions. Thus, OATP1A2 may be a pharmacological target for prostate cancer treatment. © 2012 Elsevier Inc.
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Izumi, Kouji ; Chang, Chawnshang
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Inflammatory cytokines and chemokines released by macrophages in the prostate cancer microenvironment may signal via the
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androgen receptor (AR ) to influence tumor progression. In particular, macrophages appear to promote tumorigenesis by altering the chemokine (C-C motif) ligand 4 (CCL4)/AR signaling axis. This process can be blocked by AS C-J9®, an enhancer of AR degradation. AS C-J9® also inhibits the CCL2-dependent, signal transducer and activator of transcription 3 (STAT3)-mediated pro-metastatic signaling cascade that is generally activated by androgen deprivation therapy. Thus, targeting inflammatory cytokines signaling via the AR , with AS C-J9®, represents a promising therapeutic approach against prostate cancer progression. © 2013 Landes Bioscience.
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Izumi, Kouji ; Chang, Chawnshang
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Inflammatory cytokines and chemokines released by macrophages in the prostate cancer microenvironment may signal via the
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androgen receptor (AR ) to influence tumor progression. In particular, macrophages appear to promote tumorigenesis by altering the chemokine (C-C motif) ligand 4 (CCL4)/AR signaling axis. This process can be blocked by AS C-J9®, an enhancer of AR degradation. AS C-J9® also inhibits the CCL2-dependent, signal transducer and activator of transcription 3 (STAT3)-mediated pro-metastatic signaling cascade that is generally activated by androgen deprivation therapy. Thus, targeting inflammatory cytokines signaling via the AR , with AS C-J9®, represents a promising therapeutic approach against prostate cancer progression. © 2013 Landes Bioscience.
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| 6.
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Izumi, Kouji ; Lin, Wen-Jye ; Miyamoto, Hiroshi ; Huang, Chiung-Kuei ; Maolake, Aerken ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Namiki, Mikio
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Purpose Prostate-specific antigen (PSA) is a useful biomarker of prostate cancer (PCa). High-risk localized PCa is defin
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ed using T stage, Gleason score (GS), and PSA. However, PSA level defining high-risk PCa is at most 20 ng/mL. In PCa patients with high PSA, it is unclear whether PSA itself can be a prognostic factor. Methods Of 642 patients who were diagnosed as PCa, 90 patients with PSA > 100 ng/mL were retrospectively analyzed. Patients were divided into three groups according to PSA level: very high (>1,000 ng/mL), moderately high (200-1,000 ng/mL), and slightly high (100-200 ng/mL). Results There were no significant differences in overall survival or PCa-specific survival (PCaSS) among the three groups. Regardless of PSA level, high M stage and GS significantly reduced PCaSS. When the risk classification was made using M stage and GS (high risk = M1 and GS ≥ 9, low risk = M0 and GS < 9, and intermediate risk = others), PCaSS was significantly different among high-, intermediate-, and low-risk groups with 5-year survival rates of 58.2, 80.6, and 100 %, respectively. Although there were no differences in treatment performed during the castration-resistant stage, patients undergoing alternative anti-androgen and zoledronic acid treatment had better PCaSS after being castration-resistant. Conclusions As PSA could not be a prognostic factor in PCa patients with high PSA > 100 ng/mL, the novel risk classification using M stage and GS may help clinicians to predict PCaSS and to plan follow-up schedules after diagnosis. © 2014 Springer-Verlag Berlin Heidelberg.
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| 7.
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Takemura, Akihiro ; Togawa, Kumiko ; Yokoi, Tomohiro ; Ueda, Shinichi ; Noto, Kimiya ; Kojima, Hironori ; Isomura, Naoki ; Kumano, Tomoyasu
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In volumetric modulated arc therapy (VMAT) for prostate cancer, a positional and rotational error correction is performe
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d according to the position and angle of the prostate. The correction often involves body leaning, and there is concern regarding variation in the dose distribution. Our purpose in this study was to evaluate the impact of body pitch rotation on the dose distribution regarding VMAT. Treatment plans were obtained retrospectively from eight patients with prostate cancer. The body in the computed tomography images for the original VMAT plan was shifted to create VMAT plans with virtual pitch angle errors of ±1.5° and ±3°. Dose distributions for the tilted plans were recalculated with use of the same beam arrangement as that used for the original VMAT plan. The mean value of the maximum dose differences in the dose distributions between the original VMAT plan and the tilted plans was 2.98 ± 0.96 %. The value of the homogeneity index for the planning target volume (PTV) had an increasing trend according to the pitch angle error, and the values of the D95 for the PTV and D2ml, V50, V60, and V70 for the rectum had decreasing trends (p < 0.05). However, there was no correlation between differences in these indexes and the maximum dose difference. The pitch angle error caused by body leaning had little effect on the dose distribution; in contrast, the pitch angle correction reduced the effects of organ displacement and improved these indexes. Thus, the pitch angle setup error in VMAT for prostate cancer should be corrected. © 2016 Japanese Society of Radiological Technology and Japan Society of Medical Physics<br />Embargo Perios 12 months
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| 8.
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Izumi, Kouji ; Mizokami, Atsushi ; Lin, Hsiu-Ping ; Ho, Hui-Min ; Iwamoto, Hiroaki ; Maolake, Aerken ; Natsagdorj, Ariunbold ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Miyamoto, Hiroshi ; Huang, Chiung-Kuei ; Namiki, Mikio ; Lin, Wen-Jye
概要:
Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/andro
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gen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone.
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| 9.
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Maolake, Aerken ; Izumi, Kouji ; Shigehara, Kazuyoshi ; Natsagdorj, Ariunbold ; Iwamoto, Hiroaki ; Kadomoto, Suguru ; Takezawa, Yuta ; Machioka, Kazuaki ; Narimoto, Kazutaka ; Namiki, Mikio ; Lin, Wen-Jye ; Wufuer, Guzailinuer ; Mizokami, Atsushi
概要:
Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and
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CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.
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| 10.
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Shigehara, Kazuyoshi ; Mizokami, Atsushi ; Komatsu, Kazuto ; Koshida, Kiyoshi ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Background: We evaluated the efficacy and complications of high dose rate (HDR) brachytherapy using
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iridium-192 (192Ir) combined with external beam radiotherapy (EBRT) in patients with prostate cancer. Methods: Ninety-seven patients underwent 192Ir HDR brachytherapy combined with EBRT at our institution between February 1999 and December 2003. Of these, 84 patients were analysed in the present study. 192Ir was delivered three times over a period of 2 days, 6 Gy per time, for a total dose of 18 Gy. Interstitial application was followed by EBRT at a dose of 44 Gy. Progression was defined as three consecutive prostate-specific antigen (PSA) rises after a nadir according to the American Society for Therapeutic Radiology and Oncology criteria. The results were classified into those for all patients and for patients who did not undergo adjuvant hormone therapy. Results: The 4-year overall survival of all patients, the nonadjuvant hormone therapy group (NAHT) and the adjuvant hormone therapy group (AHT) was 87.2%, 100%, and 70.1%, respectively. The PSA progression-free survival rate of all patients, NAHT, and AHT was 82.6%, 92.0%, and 66.6%, respectively. Of all patients, the 4-year PSA progression-free survival rates of PSA < 20 and PSA ≥ 20 groups were 100%, and 46.8%, respectively. According to the T stage classification, PSA progression-free survival rates of T1c, T2, T3, and T4 were 100%, 82.8%, 100%, and 12.1%, respectively. Prostate-specific antigen progression-free survival rates of groups with Gleason scores (GS) < 7 and GS ≥ 7 were 92.8% and 60.1%, respectively. Of NAHT, PSA progression-free survival of PSA < 20 was 100% vs 46.8% for PSA ≥ 20, that of T1c was 100% vs 75% for T2, and that of GS < 7 was 100% vs 75% for GS ≥ 7. No significant intraoperative or postoperative complications requiring urgent treatment occurred except cerebellum infarction. Conclusions: 192Ir HDR brachytherapy combined with EBRT was as effective as radical prostatectomy and had few associated complications。
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