Kazutoshi Fujita

Osaka City University, Ōsaka, Ōsaka, Japan

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Publications (69)207.84 Total impact

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    ABSTRACT: To present mature results of high-dose-rate brachytherapy (HDR-BT) as monotherapy for intermediate- and high-risk prostate cancer.
    International Journal of Radiation OncologyBiologyPhysics 06/2015; DOI:10.1016/j.ijrobp.2015.05.044 · 4.18 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression and function in tumor development and progression. We previously identified up-regulated miRNAs in clear cell renal cell carcinoma (ccRCC) compared to matched-pair normal kidney by microarray. Here, we identify miRNAs that are up-regulated in ccRCC and are also correlated with survival and/or recurrence. Twenty-four samples from ccRCC patients who underwent nephrectomies between 2011 and 2012 were divided into two groups: one of eleven patients who experienced recurrence (Group 1), and one of thirteen patients with no evidence of disease (Group 2) 2 years after surgery. Analyzing 22 miRNAs that were up-regulated in ccRCC in our previous study, we identify five miRNAs that were statistically up-regulated in Group 1 versus Group 2 by quantitative real-time PCR. We then evaluated these miRNAs in an independent cohort of 159 frozen ccRCC samples. High levels of miR-27a-3p (p < 0.01) correlated with a worse progression-free survival rate. Multivariate analysis revealed that miR-27a-3p was an independent predictive factor for recurrence. For functional analysis, miR-27a-3p controlled cell proliferation, migration and invasion in RCC cell lines. MiR-27a-3p could act as oncogenic miRNA and may be a candidate for targeted molecular therapy in ccRCC.
    Oncotarget 05/2015; · 6.63 Impact Factor
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    ABSTRACT: A 64-year-old man presented with right renal cell carcinoma with tumoral thrombosis in the inferior vena cava. Transthoracic echocardiography and contrast-enhanced computed tomography 2 days before the scheduled surgery revealed a tumoral thrombus floating in the right atrium. The tumoral thrombus measured 2 by 3 centimeters and the patient was asymptomatic. An emergency surgey was performed to remove the tumoral thrombus from the right atrium and a temporary inferior vena cava filter was placed. Right nephrectomy and thrombectomy were carried out 3 weeks later. Pathological diagnosis made from both surgical specimens was clear cell renal cell carcinoma, and the tumoral thrombus was considered to have separated from the tumor thrombus in inferior vena cava. No obvious recurrence has been observed for 6 months after the surgery.
    Hinyokika kiyo. Acta urologica Japonica 05/2015; 61(5):207-10.
  • The Journal of Urology 04/2015; 193(4):e552. DOI:10.1016/j.juro.2015.02.1521 · 3.75 Impact Factor
  • The Journal of Urology 04/2015; 193(4):e69. DOI:10.1016/j.juro.2015.02.221 · 3.75 Impact Factor
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    ABSTRACT: Recent studies have reported that bone marrow-derived cells (BMDCs), which are recruited to sites of tissue injury and inflammation, can differentiate into epithelial cells, such as liver, lung, gastrointestinal tract, and skin cells. We investigated the role of BMDCs in contributing to regeneration of injured prostate epithelium. Using chimera rats that received allogenic bone marrow grafts from green fluorescent protein (GFP) transgenic rats after lethal whole-body irradiation, we investigated the existence of epithelial marker-positive BMDCs in injured prostate tissue caused by transurethral injection of lipopolysaccharide. Prostate tissues were harvested 2 weeks after transurethral lipopolysaccharide injection. Immunofluorescence staining showed that some cells in the stroma co-expressed GFP and pan-cytokeratin, which suggested the existence of epithelial marker-positive BMDCs. To confirm the existence of such cells, we collected bone marrow-derived non-hematopoietic cells (GFP+/CD45- cells) from the prostate by fluorescence-activated cell sorter analysis and analyzed the characteristics of the GFP+/CD45- cells. The number of cells in this population significantly increased from 0.042% to 0.492% compared with normal prostate tissue. We found by immunofluorescent analysis and RT-PCR that GFP+/CD45- cells expressed cytokeratin, which suggested that these cells have some features of epithelial cells. In the prostate obtained from the chimera rats 34 weeks after lipopolysaccharide injection, GFP- and cytokeratin-positive cells were observed in the prostate gland, which suggested that some of the cells in the prostate gland regenerated after prostate inflammation derived from bone marrow. BMDCs might be able to differentiate into prostate epithelial cells after prostatic injury. Prostate 9999: 1-9, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 02/2015; 191(4). DOI:10.1002/pros.22962 · 3.57 Impact Factor
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    ABSTRACT: Objectives To evaluate the expression and prognostic significance of endoglin in patients with upper urinary tract urothelial carcinoma.MethodszArchival formalin-fixed and paraffin-embedded tissues from 99 cases of primary upper urinary tract urothelial carcinomas treated with nephroureterectomy were retrieved. Tissue microarrays were constructed with triplicate tumor samples and paired non-neoplastic urothelium. Tissue microarrays were analyzed using immunohistochemistry for endoglin, and the associations between clinicopathological parameters and outcome were studied.ResultsEndoglin expression was significantly higher in the endothelium of upper urinary tract urothelial carcinomas than in paired benign urothelium (P < 0.001). Endoglin expression was not associated with pathological T stage or tumor grade, and it was not associated with increased hazard ratios for cancer-specific mortality, tumor recurrence in the lymph node or distant metastasis. However, expression of endoglin was significantly associated with intravesical recurrence, when adjusting for other relevant clinicopathological variables (P = 0.015).Conclusions Endoglin is overexpressed in the endothelium of upper urinary tract urothelial carcinomas when compared with normal urothelium, and this overexpression seems to be associated with a higher risk of intravesical recurrence. Therefore, endoglin could be a biomarker for the prediction of intravesical recurrence, as well as a potential therapeutic target.
    International Journal of Urology 01/2015; 191(4). DOI:10.1111/iju.12719 · 1.80 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. To identify a therapeutic target for ccRCC, microRNA (miRNA) expression signatures from ccRCC clinical specimens were analyzed. miRNA microarray and real-time PCR analyses revealed that miR-629 expression was significantly upregulated in human ccRCC compared to adjacent non-cancerous renal tissue. Functional inhibition of miR-629 by a hairpin miRNA inhibitor suppressed ccRCC cell motility and invasion. Mechanistically, miR-629 directly targeted tripartite motif-containing 33 (TRIM33), which inhibits the TGF-beta/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathological stages and grades. The miR-629 inhibitor significantly suppressed TGF-beta-induced Smad activation by upregulating TRIM33 expression and subsequently inhibited the association of Smad2/3 and Smad4. Moreover, a miR-629 mimic enhanced the effect of TGF-beta on the expression of epithelial-mesenchymal transition (EMT)-related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGF-beta/Smad signaling pathway via TRIM33 in ccRCC. Implications: This study suggests that miR-629 has biomarker potential through its ability to regulate TGF-beta/Smad signaling and accelerate ccRCC cell motility and invasion.
    Molecular Cancer Research 11/2014; 13(3). DOI:10.1158/1541-7786.MCR-14-0300 · 4.50 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. To identify a therapeutic target for ccRCC, microRNA (miRNA) expression signatures from ccRCC clinical specimens were analyzed. miRNA microarray and real-time PCR analyses revealed that miR-629 expression was significantly upregulated in human ccRCC compared to adjacent non-cancerous renal tissue. Functional inhibition of miR-629 by a hairpin miRNA inhibitor suppressed ccRCC cell motility and invasion. Mechanistically, miR-629 directly targeted tripartite motif-containing 33 (TRIM33), which inhibits the TGF-beta/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathological stages and grades. The miR-629 inhibitor significantly suppressed TGF-beta-induced Smad activation by upregulating TRIM33 expression and subsequently inhibited the association of Smad2/3 and Smad4. Moreover, a miR-629 mimic enhanced the effect of TGF-beta on the expression of epithelial-mesenchymal transition (EMT)-related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGF-beta/Smad signaling pathway via TRIM33 in ccRCC. Implications: This study suggests that miR-629 has biomarker potential through its ability to regulate TGF-beta/Smad signaling and accelerate ccRCC cell motility and invasion.
    Molecular Cancer Research 11/2014; · 4.50 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2872-2872. DOI:10.1158/1538-7445.AM2014-2872 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):5197-5197. DOI:10.1158/1538-7445.AM2014-5197 · 9.28 Impact Factor
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    ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common histologically-defined subtype of renal cell carcinoma (RCC). To define the molecular mechanism in the progression of ccRCC, we focused on LOX-like protein 2 (LOXL2), which is critical for the first-step in collagen and elastin crosslinking. Using exon array analysis and quantitative validation, LOXL2 was shown to be significantly upregulated in clinical specimens of human ccRCC tumor tissues, compared to adjacent non-cancerous renal tissues, and this elevated expression correlated with the pathological stages of ccRCC. RNAi-mediated knockdown of LOXL2 resulted in marked suppression of stress-fiber and focal adhesion formation in ccRCC cells. Moreover, LOXL2 siRNA knockdown significantly inhibited cell growth, migration, and invasion. Mechanistically, LOXL2 regulated the degradation of both integrins alpha5 (ITGAV5) and beta1 (ITGB1) via protease- and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin alpha5 correlated with the pathological tumor grades. In conclusion, LOXL2 is a potent regulator of integrin alpha5 and integrin beta1 protein levels and functions in a tumor-promoting capacity in ccRCC. Implications: This is the first report demonstrating that LOXL2 is highly expressed and involved in ccRCC progression by regulating the levels of integrins alpha5 and beta1.
    Molecular Cancer Research 08/2014; DOI:10.1158/1541-7786.MCR-14-0233 · 4.50 Impact Factor
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    ABSTRACT: BACKGROUND Fucosylation is an oligosaccharide modification associated with cancer and inflammation, which is catalyzed by fucosyltransferases. Fucosylated haptoglobin (Fuc-Hpt) has been identified as a novel biomarker for pancreatic cancer.In this study, we evaluated serum Fuc-Hpt as a biomarker for prostate cancer, and investigated the expression of fucosyltransferases and haptoglobin in prostate cancer cell lines.METHODS We measured the preoperative serum Fuc-Hpt levels in 98 patients who underwent radical prostatectomy (RP) using an established lectin-antibody ELISA. Fucosyltransferase and haptoglobin mRNA and protein expressions in prostate cancer cell lines were determined using quantitative PCR and Western blotting.RESULTSSerum Fuc-Hpt levels were significantly associated with Gleason score (GS), but not prostate-specific antigen (PSA) levels. The area under the receiver-operator characteristics curve (AUC) for the prediction of GS ≥7 in prostatectomy specimens by Fuc-Hpt was 0.753, in contrast to the PSA AUC of 0.561 and the PSAD AUC of 0.558. The Fuc-Hpt AUC for the prediction of GS upgrade from GS 6 at biopsy to GS ≥7 after RP was 0.689, in contrast to the PSA AUC of 0.588 and PSAD AUC of 0.557. Multivariable analysis revealed that Fuc-Hpt levels were significantly associated with biochemical recurrence after prostatectomy. A high expression of alpha-(1–6) fucosyltransferase (FUT8) and haptoglobin was observed in prostate cancer cell line, suggesting that certain kinds of prostate cancer cells produce Fuc-Hpt.CONCLUSION Elevated serum Fuc-Hpt level could be a novel cancer biomarker for predicting the prognosis of patients with prostate cancer, particularly those with high GSs. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 07/2014; 74(10). DOI:10.1002/pros.22824 · 3.57 Impact Factor
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    ABSTRACT: Leiomyosarcomas of the spermatic cord are rare tumors which cause significant morbidity and mortality. We report a case of leiomyosarcoma in a 67-year-old man who presented with a left scrotal mass. Left orchiectomy with high ligation of the spermatic cord was performed with clinical diagnosis of scrotal tumor. The pathological examination revealed leiomyosarcoma arising from the spermatic cord. He was free of disease two years postoperatively.
    Hinyokika kiyo. Acta urologica Japonica 06/2014; 60(6):299-301.
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    ABSTRACT: This study aimed to identify preoperative parameters for predicting cancer-specific survival (CSS) in patients with upper urinary tract urothelial carcinoma (UTUC) who have undergone radical nephroureterectomy (RNU). The preoperative clinical and laboratory records of 357 UTUC patients who underwent RNU at three different institutions were retrospectively reviewed (256, training set; 101, test set). Univariate and multivariate analyses were performed on the training set data to identify preoperative prognostic factors, using which a risk stratification model was developed. The model was validated using test set data. In univariate analysis, clinical T stage classification and preoperative concentrations of hemoglobin, C-reactive protein, sodium, and albumin showed significant association with CSS. Multivariate analysis showed that low preoperative sodium and hemoglobin concentrations were significantly associated with a poor prognosis. A risk stratification model was developed using the preoperative sodium (<141 mEq/L) and hemoglobin concentrations (below normal). Three subgroups were formed depending on the presence of no (favorable group), one (intermediate), or two (poor) prognostic factors, and the 5-year CSS estimates were found to be 96.5, 75.5, and 47.0 %, respectively (P < 0.01). The risk model was significantly associated with the adverse pathological findings of stage pT3 or more and lymphovascular invasion (P = 0.005). We identified low preoperative sodium and hemoglobin concentrations as prognostic factors for patients with UTUC treated with RNU. Our risk stratification model may help physicians design a therapeutic strategy.
    International Journal of Clinical Oncology 04/2014; 20(1). DOI:10.1007/s10147-014-0695-1 · 2.17 Impact Factor
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    ABSTRACT: A 32-year-old man was referred to our hospital for treatment of left renal cystic tumor, which was detected by computed tomographic (CT) scan 3 years ago. CT scan showed a multilocular cyst (5 cm in diameter) with a solid tumor in the left kidney which was enhanced with contrast. There was no evidence of extrarenal invasion or distant metastasis. We performed retroperitoneal laparoscopic radical nephrectomy. Pathological examinations revealed a cellular arrangement specific to carcinoid tumor and positive for CD56 (NCAM) and neuron-specific enolase. The cell proliferation rate was estimated to be under 2% with Ki67 staining. The pathological diagnosis was renal neuroendocrine tumor (carcinoid). At the 9-month follow up, he had no evidence of local recurrence or metastasis.
    Hinyokika kiyo. Acta urologica Japonica 11/2013; 59(11):723-7.
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    ABSTRACT: Upper tract urothelial carcinoma (UTUC) accounts for 5% to 10% of all urothelial carcinomas. Despite many shared features, key clinical and molecular genetic differences between upper tract and bladder urothelial carcinomas are becoming apparent. We have previously demonstrated alterations of mammalian target of rapamycin (mTOR) pathway in bladder carcinoma with a potential impact on biological behavior. In the current study, we evaluated the expression status and prognostic significance of mTOR pathway members in UTUC. Archival formalin-fixed and paraffin-embedded tissues from 99 primary UTUCs were retrieved from one of the authors' institution. Tissue microarrays were constructed with triplicate tumor samples and paired nonneoplastic urothelium. Tissue microarrays were analyzed using immunohistochemistry for mTOR pathway members: PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, and related markers p27 and c-MYC; correlation with clinicopathologic parameters and outcome was performed. We found significantly lower expression of PTEN, phos-AKT, phos-mTOR, phos-S6, phos-4EBP1, p27, and c-MYC in UTUC compared with paired benign urothelium (P < .0005). We found a strong positive correlation between PTEN and phos-AKT. Moderate correlation was observed between phos-mTOR and phos-S6, PTEN and p27, phos-AKT and p27, phos-S6 and p27, phos-mTOR and c-MYC, phos-S6 and c-MYC, and p27 and c-MYC. None of the evaluated biomarkers were associated with increased hazard ratios for tumor recurrence or for cancer-specific mortality, when adjusting for relevant clinicopathologic variables. Dysregulation of the mTOR pathway was observed in UTUC compared with normal urothelium, implicating a potential pathogenic role in tumor development. In our cohort, expression of the evaluated biomarkers had no prognostic value.
    Human pathology 09/2013; 44(12). DOI:10.1016/j.humpath.2013.07.008 · 2.81 Impact Factor
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    ABSTRACT: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.
    PLoS ONE 09/2013; 8(9):e74313. DOI:10.1371/journal.pone.0074313 · 3.53 Impact Factor
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    ABSTRACT: To determine whether low-grade systemic inflammation is associated with prostatic enlargement/benign prostatic hyperplasia. Prostate volume was measured by transrectal ultrasonography in 576 Japanese men. The association between prostate volume and routine clinical inflammatory markers (C-reactive protein level, white blood cell count, or the differential white cell count [neutrophils, lymphocytes, basophils, eosinophils, and monocytes]) were analyzed. Contributors to prostate volume were identified in univariate and multivariable linear regression models. Prostate volume was found to have a positive association with serum prostate-specific antigen level (P < 0.001), white blood cell count (P = 0.027) and absolute neutrophil count (P = 0.010). In univariate linear regression models, a large prostate volume was associated with older age, higher prostate-specific antigen, and higher white blood cell and neutrophil counts. A multivariable model adjusted for age, prostate-specific antigen, and C-reactive protein showed that the white blood cell count and the neutrophil count were independently associated with prostate volume. An increased white blood cell count was also associated with higher total International Prostatic Symptom Scores (P < 0.001). White blood cell count seems to be associated with the degree of prostate enlargement and lower urinary tract symptoms. Chronic low-grade systemic inflammation might be involved in the etiology of benign prostatic hyperplasia.
    International Journal of Urology 08/2013; 21(3). DOI:10.1111/iju.12243 · 1.80 Impact Factor
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    ABSTRACT: To analyze the presence of immature vessels as a predictive factor of prognosis in patients with renal cell carcinoma. Tissue samples were obtained from 50 renal cell carcinoma patients who underwent radical nephrectomy, and the blood vessels were stained using antibodies to cluster of differentiation 34 and α-smooth muscle actin. Immature vessels were defined as those positive for cluster of differentiation 34, and mature vessels as those positive for both cluster of differentiation 34 and α-smooth muscle actin. The extent of vascularization was quantified by calculating the microvessel area and microvessel density. The microvessel area of immature vessels was positively associated with tumor grade (P < 0.0001), T stage (P < 0.0001) and American Joint Committee on Cancer stage (P < 0.0001), and was significantly higher in tumors with metastasis than in those without metastasis (P < 0.0001). The microvessel density did not associate with tumor grade or T stage. The disease-free survival and overall survival were significantly shorter in patients with high microvessel area. The microvessel area of immature vessels seems to be associated with renal cell carcinoma aggressiveness, suggesting this might be considered as a novel prognostic factor in patients with these tumors.
    International Journal of Urology 08/2013; 21(2). DOI:10.1111/iju.12231 · 1.80 Impact Factor

Publication Stats

465 Citations
207.84 Total Impact Points

Institutions

  • 2005–2015
    • Osaka City University
      • • Department of Urology
      • • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2010–2014
    • Osaka General Medical Center
      Ōsaka, Ōsaka, Japan
  • 2006–2014
    • Osaka University
      • Division of Urology
      Suika, Ōsaka, Japan
  • 2008–2011
    • Johns Hopkins Medicine
      • Department of Urology
      Baltimore, Maryland, United States
  • 2009
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2004–2007
    • Osaka Police Hospital
      Ōsaka, Ōsaka, Japan