H Kanayama

The University of Tokushima, Tokusima, Tokushima, Japan

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Publications (79)194.09 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: We conducted this study to determine whether substitution with anti-androgen (SOA) and tegafur-uracil (a pro‑drug of 5-FU) combination therapy is more effective than SOA alone after relapse from initial hormonal therapy. Patients who were histologically confirmed and relapsed after initial hormonal therapy were included. All patients were randomly allocated into two groups: SOA alone (group A) or SOA combined with tegafur-uracil (group B). The mRNA expression of four enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phospho-ribosyltransferase (OPRT) and thymidine phosphorylase (TP), in prostate cancer cells was analyzed by quantitative reverse-transcription polymerase chain reaction. Fifty-two patients were enrolled in this study. The median age was 77 (range: 47-92) years. The PSA response rate in group B (61.5%) tended to be higher compared to that in group A (34.6%) (p=0.095). Group B (median: 15.9 months) had a significantly longer time to PSA progression (TTP) compared to group A (6.4 months) (p=0.014). In patients with a lower TS expression or a higher OPRT expression, group B demonstrated a higher PSA response rate compared to group A (p=0.019 and p=0.041, respectively). In addition, in the patients with a lower TS expression, group B demonstrated a significantly longer TTP compared to group A (p=0.018). There were no severe adverse events in either treatment group. After relapse from initial hormonal therapy, SOA combined with tegafur-uracil is effective and well tolerated. The TS mRNA expression level may be a predictive factor for this combination therapy.
    International Journal of Oncology 06/2013; · 2.66 Impact Factor
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    ABSTRACT: OBJECTIVE: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. METHODS: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. RESULTS: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis. CONCLUSIONS: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.
    Japanese Journal of Clinical Oncology 04/2013; · 1.90 Impact Factor
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    ABSTRACT: Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for RCC patients. RNAi-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G1 phase cell cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis.
    Cancer Research 09/2012; · 8.65 Impact Factor
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    ABSTRACT: The aims of the present study were to: (i) develop a clinically useful prognostic classification in Asian patients with metastatic renal cell carcinoma (RCC) by combining metastatic features with several pretreatment parameters; and (ii) evaluate the validity of this prognostic classification. Baseline characteristics and outcomes were collected for 361 patients who underwent interferon-α-based therapy between 1995 and 2005. Relationships between overall survival (OS) and potential prognostic factors were assessed using Cox's proportional hazard model. The predictive performance of the model was evaluated using bootstrap resampling procedures and by using an independent dataset obtained from randomly selected institutions. The predictive accuracy was measured using the concordance index (c-index). Four factors were identified as independent prognostic factors: time from initial diagnosis to treatment, anemia, elevated lactate dehydrogenase (LDH), and poor prognostic metastatic group (liver only, bone only, or multiple organ metastases). Each patient was assigned to one of three risk groups: favorable risk (none or one factor; n = 120), in which median OS was 51 months; intermediate risk (two factors; n = 101), in which median OS was 21 months; and poor risk (three or four factors; n = 102), in which median OS was 10 months. The c-index was 0.72 in the original dataset and 0.72 in 500 random bootstrap samples. In the independent dataset for external validation, the c-index was 0.73. Thus, the new prognostic classification is easily applicable for Asian patients with previously untreated metastatic RCC and should be incorporated into patient care, as well as clinical trials performed in Asia.
    Cancer Science 05/2012; 103(9):1695-700. · 3.48 Impact Factor
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    ABSTRACT: In 2003, the Japanese Urological Association (JUA) and Japanese Society of Endourology (JSE) established a urological laparoscopic skill qualification system, called the Endoscopic Surgical Skill Qualification System in Urological Laparoscopy of JUA and JSE (ESSQSJJ). The main goal of the system is to decrease the prevalence of complications associated with laparoscopic surgery. To validate the qualification system, perioperative outcome and the prevalence of complications in different types of urological laparoscopic surgery performed by accredited surgeons were evaluated. One hundred thirty-six surgeons who obtained the qualification in 2004 were prospectively asked to submit intraoperative and postoperative data of their latest 20 cases at the end of 2009, along with the number of laparoscopic urological surgeries performed in each year for a 5-year period (2004-2009). Intraoperative and postoperative complications were graded according to the Satava classification and modified Clavien classification, respectively. Data of 2,590 urological laparoscopic surgeries of 130 surgeons, including 904 laparoscopic radical nephrectomies, 430 laparoscopic nephroureterectomies, 390 laparoscopic adrenalectomies, 320 laparoscopic radical prostatectomies, and 170 laparoscopic partial nephrectomies, were analyzed. Complications were noted in 97 (3.7%) patients. Major intraoperative complications (grade II or III) occurred in 32 (1.2%) patients, and major postoperative complications (grade III or higher) occurred in 24 (0.9%) patients. The prevalence of conversion to open surgery, allogeneic transfusion, and perioperative mortality was 2.5%, 1.6%, and 0%, respectively. The number of surgeries performed by each qualified surgeon or the role of the surgeon (main operator vs. mentor/instructor) in the surgery did not affect the prevalence of intraoperative complications or postoperative complications. The open conversion rate was significantly higher in surgeons with a low surgical volume. ESSQSJJ can ensure urological laparoscopic surgeons who can perform various types of urological laparoscopic surgeries with a low prevalence of perioperative complications and reasonable outcomes.
    Surgical Endoscopy 12/2011; 26(6):1656-63. · 3.43 Impact Factor
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    ABSTRACT: To examine plakophilin proteins (Pkp) and 3 expression levels in bladder cancer, in particular their levels during cellular growth and invasion. Pkp is associated with the binding of cadherin to intermediate filaments of the cytoskeleton. The relative mRNA and protein expression levels of Pkp2 and 3 in bladder cancer cell lines were determined using quantitative real-time polymerase chain reaction and Western blot analyses. The cellular localization of Pkp2 and 3 proteins in bladder cancer cells was also assayed using immunohistochemistry. The proliferation and invasive activities of bladder cancer cells were evaluated using cell growth and in vitro cell invasion assays, and were compared with those of bladder cancer cells treated with Pkp2 and 3 small interfering RNAs. Pkp2 mRNA and protein levels were elevated, and those of Pkp3 were reduced, in bladder cancer cells that are known to exhibit increased proliferation and invasive activity. Pkp2/3 protein expression was predominantly observed in the cytoplasm of invasive bladder cancer cells and tissues. Pkp2 knockdown inhibited, and Pkp3 knockdown enhanced, invasion of bladder cancer cells, but these knockdowns did not alter cell proliferation. We conclude that high Pkp2, and low Pkp3, expression is associated with bladder cancer cell invasion and that neither Pkp2 nor Pkp3 is associated with cell proliferation. We further hypothesize that accumulation of Pkp2 and 3 in the cell cytoplasm, rather than their recruitment to the cell membrane, is related to an increased ability of the tumor to invade and metastasize.
    Urology 11/2011; 79(1):240.e1-8. · 2.42 Impact Factor
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    ABSTRACT: We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.
    International Journal of Oncology 03/2011; 38(3):665-76. · 2.66 Impact Factor
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    ABSTRACT: In this study, we investigated the synergistic mechanism of anti-androgen and 5-fluorouracil (5-FU) combination therapy against castration-resistant prostate cancer (CRPC). Four prostate cancer cell lines, LNCaP, 22Rv1, DU145 and PC3, were examined for their growth dependency on androgens and the insulin-like growth factor 1 (IGF1). We assessed the expression changes of certain growth factor receptors and regulating proteins when treated with 5-FU, and found that 5-FU increased the expression of the IGF-binding protein 3 (IGFBP3). Furthermore, 5-FU inhibited the phosphorylation of Akt and p70 S6K, while the knockdown of IGFBP3 reduced the levels of poly (ADP-ribose) polymerase cleaved by 5-FU in PC3 cells. Therefore, the up-regulation of IGFBP3 by 5-FU not only inhibits cell growth by reducing the IGF1 signal but also induces apoptosis in PC3 cells. The synergistic effect of bicalutamide and 5-FU on 22Rv1 cells was reduced by IGFBP3 gene silencing using small-interfering RNA. These results suggest that the up-regulation of IGFBP3 induced by 5-FU plays an important role in the potent anti-tumor effect of 5-FU combined with anti-androgens on CRPC. Androgen-deprivation therapy combined with 5-FU could therefore be an appropriate therapy for CRPC patients.
    International Journal of Oncology 03/2011; 38(6):1489-500. · 2.66 Impact Factor
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    ABSTRACT: It is no exaggeration to say that the success of molecular targeted therapy for advanced renal cell carcinoma (RCC) depends on the measures taken to deal with adverse events (AEs). We recently analyzed the AEs arising from the use of molecular targeted drugs in patients with advanced RCC at the Department of Urology at Yamagata University Hospital.
    Japanese Journal of Clinical Oncology 03/2011; 41(3):i18. · 1.90 Impact Factor
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    ABSTRACT: The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood. Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay. When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA. Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.
    British Journal of Cancer 02/2011; 104(3):505-13. · 5.08 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
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    ABSTRACT: To elucidate the incidence and mechanisms of sunitinib-induced thyroid atrophy, we investigated serial volumetric and functional changes, and evaluated histological changes of the thyroid gland in metastatic renal cell carcinoma patients who received sunitinib. Thyroid volume (by computed tomography volumetry) and thyroid function were measured at baseline, during the treatment, and at post-treatment periods. Histological evaluation of the thyroid gland was performed in four autopsied patients. The median reduction rate in thyroid volume at last evaluation during sunitinib treatment was 30% in all 17 patients. The incidence of hypothyroidism during sunitinib treatment was significantly higher in the high reduction rate group (n=8; more than 50% reduction in volume) than in the low reduction rate group (n=9; less than 50% reduction in volume). Half of the patients in the high reduction rate group exhibited a transient thyroid-stimulating hormone suppression, suggesting thyrotoxicosis during sunitinib treatment. Histological evaluation demonstrated atrophy of thyroid follicles and degeneration of follicular epithelial cells without critical diminution of vascular volume in the thyroid gland. Thyroid atrophy is frequently observed following sunitinib treatment and may be brought about by sunitinib-induced thyrotoxicosis or the direct effects of sunitinib that lead to degeneration of thyroid follicular cells.
    British Journal of Cancer 01/2011; 104(2):241-7. · 5.08 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Urology 01/2011; 78(3). · 2.42 Impact Factor
  • Hiroomi Kanayama
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    ABSTRACT: Two molecular targeted drugs, sorafenib and sunitinib, were approved for treatment against advanced renal cell carcinoma in 2008 in Japan. These two drugs can be orally administered as different from interferon-alpha administered subcutaneously or interleukin-2 intravenously. In the near future, everolimus will also be approved in Japan. Moreover, other vascular endothelial growth factor receptor inhibitors will be up available. Molecular targeted drugs are associated with different adverse events from classical anticancer drugs. Control of adverse events is important to obtain maximum effectiveness of these molecular targeted drugs. Neoadjuvant therapy with these drugs for unresectable primary tumor or large tumor in solitary kidney may also be effective to complete nephrectomy or nephron spearing surgery. Treatment strategy for advanced renal cell carcinoma has been changing dramatically after introduction of these molecular targeted drugs.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2010; 37(7):1208-13.
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    ABSTRACT: To examine actinin-4 expression levels in bladder cancer, in particular its levels during cellular growth and invasion. Actinin-4 is an actin-binding protein that is associated with cell motility and cancer metastasis. Relative messenger ribonucleic acid (mRNA) and protein expression of actinin-4 in normal bladder and bladder cancer cell lines was determined by quantitative real-time polymerase chain reaction and Western blot analysis. Actinin-4 expression was also localized in bladder cancer cells and tissues using immunohistochemistry. The growth and invasion activity of bladder cancer cells was evaluated using cell growth and in vitro cell invasion assays, and compared with that of bladder cancer cells treated with actinin-4 small interfering ribonucleic acids. Actinin-4 mRNA and protein levels were elevated in bladder cancer cells that are known to exhibit increased growth and invasion activity. Protein expression was predominantly observed in the cytoplasm of the invasive bladder cancer cells and tissues. Treatment of bladder cancer cell lines with actinin-4 small interfering ribonucleic acids suppressed the invasive potential of the cells, but did not alter their growth. The current study demonstrates that actinin-4 mRNA and protein levels are elevated in bladder cancer cells lines that exhibit increased growth and invasion activity. In addition, actinin-4 knockdown inhibited invasion of bladder cancer cells, but did not alter their growth. In conclusion, we hypothesize that the accumulation of actinin-4 in the cell cytoplasm is related to an increased susceptibility of tumor invasion and metastasis.
    Urology 12/2009; 75(2):357-64. · 2.42 Impact Factor

Publication Stats

929 Citations
86 Downloads
194.09 Total Impact Points

Institutions

  • 1992–2013
    • The University of Tokushima
      • Department of Urology
      Tokusima, Tokushima, Japan
  • 1999
    • University of Texas MD Anderson Cancer Center
      • Department of Cancer Biology
      Houston, TX, United States