Kazutoshi Fujita

Osaka City University, Ōsaka, Ōsaka, Japan

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Publications (74)238.88 Total impact

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    ABSTRACT: Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, currently used targeted therapy for malignant bladder cancer is still not efficient. We focused on the miR-130 family (miR-130b, miR-301a, and miR-301b) that was significantly upregulated in bladder cancer specimens than that of the normal urothelial specimens. We analyzed the functional significance of miR-130 family using a 5637 bladder cancer cell line and revealed that miR-130 family of inhibitors suppressed cell migration and invasion by downregulating focal adhesion kinase (FAK) and Akt phosphorylation. Mechanistic analyses indicate that the miR-130 family directly targets phosphatase and tensin homolog deleted from chromosome 10 (PTEN), resulting in the upregulation of FAK and Akt phosphorylation. In clinical bladder cancer specimens, downregulation of PTEN was found to be closely correlated with miR-130 family expression levels. Overall, the miR-130 family has a crucial role in malignant progression of bladder cancer and thus the miR-130 family could be a promising therapeutic target for invasive bladder cancer.
    No preview · Article · Feb 2016 · Scientific Reports
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    ABSTRACT: A 25-year-old man was admitted to our hospital complaining of right scrotal pain and upper abdominal pain. A computed tomographic scan indicated a right scrotal mass, a huge liver mass, and multiple lung masses, although there was no enlarged retroperitoneal lymph node swelling. Laboratory tests showed severe liver and kidney dysfunction and high levels of serum α-fetoprotein (11 997 ng/ml). Although needle biopsies of the testicular and liver masses were performed, the tissues were insufficient for a pathological diagnosis. As liver and kidney function worsened, we started chemotherapy with bleomycin, etoposide, and cisplatin (BEP chemotherapy), which was modified because of the liver and renal dysfunction. We also used continuous hemodiafiltration and rasburicase to prevent tumor lysis syndrome. After induction of chemotherapy, the liver and kidney dysfunction improved immediately and the high orchiectomy was performed on day 8 after chemotherapy. The pathological diagnosis was a yolk sac tumor. He underwent four courses of the BEP regimen and five courses of the TIN regimen (paclitaxel, ifosphamide, and nedaplatin), followed by the resection of liver metastases. There was no evidence of viable cells in the resected liver and no recurrence was evident at 1 year postoperatively.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0/.
    No preview · Article · Jan 2016 · Anti-cancer drugs
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    ABSTRACT: We investigated the association between the R.E.N.A.L. nephrometry score (RNS) and the postoperative recurrence of localized renal cell carcinoma (RCC). We retrospectively analyzed a database comprising 91 patients with non-small localized RCC (pT1b-T2b) treated by radical nephrectomy at our hospital from January 2002 to March 2010. RNS was scored based on imaging findings at diagnosis. The Cox proportional hazards model was used to predict recurrence-free survival (RFS) and to calculate hazard ratio (HR). The median age at operation was 63 years (range, 30-85 years). Postoperative recurrence occurred in 19 patients (21 %). Median RNS sum was 9 (range, 5-11). High RNS sum (10-12) was significantly associated with RFS (P = 0.0012). Multivariate analysis revealed that high RNS sum [HR, 9.05; 95 % confidence interval (CI), 2.11-63.9; P = 0.0019] were significantly associated with RFS. Regarding each component of RNS, only the L component, which referred to tumor location relative to the polar line, was associated with RFS (HR, 15.0; 95 % CI, 2.68-396; P = 0.0006). RNS was associated with RFS in cases of non-small localized RCC (pT1b-2b), thus supporting its utility as a prognostic factor.
    No preview · Article · Jul 2015 · International Journal of Clinical Oncology
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    ABSTRACT: To analyze the role of adjuvant chemotherapy in lymph node-positive patients with upper tract urothelial carcinoma undergoing radical nephroureterectomy, and identified the prognostic adjuvant chemotherapy parameters. The clinicopathological records of 74 lymph node-positive upper tract urothelial carcinoma patients who underwent radical nephroureterectomy at multiple institutions were retrospectively reviewed. A total of 45 patients (60.8%) received adjuvant chemotherapy, and 29 (39.2%) underwent radical nephroureterectomy only. Kaplan-Meier analyses and Cox proportional hazard modeling were used to study the association between adjuvant chemotherapy status and both recurrence-free survival and cancer-specific survival. Estimated 5-year recurrence-free survival was 33.6% in patients undergoing radical nephroureterectomy plus adjuvant chemotherapy compared with 13.5% in patients undergoing radical nephroureterectomy only (hazard ratio 0.52; P = 0.014, log-rank test). Estimated 5-year cancer-specific survival was 42.5% in patients undergoing radical nephroureterectomy plus adjuvant chemotherapy, compared with 12.0% in patients undergoing radical nephroureterectomy only (hazard ratio 0.36; P = 0.0003, log-rank test). Multivariate analysis showed that adjuvant chemotherapy was a significant prognostic factor for cancer-specific survival (P = 0.001), but not for recurrence-free survival (P = 0.076). When patients undergoing radical nephroureterectomy plus adjuvant chemotherapy were dichotomized, based on preoperative C-reactive protein levels above or below the normal value, higher C-reactive protein levels were significantly associated with poor survival (P = 0.012). Adjuvant chemotherapy seems to improve cancer-specific survival in lymph node-positive patients with upper tract urothelial carcinoma. Preoperative C-reactive protein levels could carry a prognostic value in this setting, and lymph node-positive patients with low preoperative CRP values should be considered for adjuvant chemotherapy. Further studies are necessary to validate these observations. © 2015 The Japanese Urological Association.
    No preview · Article · Jul 2015 · International Journal of Urology
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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. From 1995 through 2012, 190 patients, 79 with intermediate-risk and 111 with high-risk prostate cancer, were treated with HDR-BT alone using 48 Gy/8 fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions over 4 to 5 days. Neoadjuvant with or without adjuvant androgen deprivation therapy was administered to 139 patients, 35 intermediate- and 104 high-risk. Median follow-up time was 92 months (range, 10-227 months), with a minimum of 2 years for surviving patients. Respective rates of cause-specific survival, overall survival, metastasis-free survival, and biochemical no evidence of disease for the intermediate-risk patients were 100%, 100%, 96%, and 93% at 5 years, and 100%, 96%, 91%, and 91% at 8 years. Corresponding rates for the high-risk patients were 97%, 93%, 84%, and 81% at 5 years, and 93%, 81%, 74%, and 77% at 8 years. The cumulative incidence of late grade 2 to 3 genitourinary toxicity was 5% at 5 years and 10% at 8 years, and that of late grade 3 was 0 at 5 years and 1% at 8 years. The cumulative incidence of late grade 2-3 gastrointestinal toxicity was 4% at 5 years and 6% at 8 years, and that of late grade 3 was 0 at 5 years and 2% at 8 years. No grade 4 or 5 toxicity was detected. Our single-institution study with a median 8-year follow-up showed that HDR-BT as monotherapy was safe and effective for patients with intermediate- and high-risk prostate cancer. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · International Journal of Radiation OncologyBiologyPhysics
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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.
    Full-text · Article · May 2015 · Oncotarget
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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.
    No preview · Article · May 2015 · Hinyokika kiyo. Acta urologica Japonica
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    Full-text · Article · Apr 2015 · The Journal of Urology
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    Full-text · Article · Apr 2015 · The Journal of Urology
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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.
    No preview · Article · Feb 2015 · The Prostate
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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.
    No preview · Article · Jan 2015 · International Journal of Urology
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    ABSTRACT: Unlabelled: 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, 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 with adjacent noncancerous 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 TGFβ/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathologic stages and grades. The miR-629 inhibitor significantly suppressed TGFβ-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 TGFβ on the expression of epithelial-mesenchymal transition-related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGFβ/Smad signaling pathway via TRIM33 in ccRCC. Implications: This study suggests that miR-629 has biomarker potential through its ability to regulate TGFβ/Smad signaling and accelerate ccRCC cell motility and invasion.
    No preview · Article · Nov 2014 · Molecular Cancer Research
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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.
    No preview · Article · Nov 2014 · Molecular Cancer Research
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    ABSTRACT: Although primary adrenal lymphoma (PAL) is thought to be extremely rare, its prognosis is much worse than that of other extranodal malignant lymphomas. There are so far about 130 reported cases in the English literature, while 186 cases have been reported in the Japanese literature. Thus, the incidence of PAL in the Japanese population may be higher than in other races. The typical characteristics of PAL in Japanese patients are similar to those previously reported in Western literature: it predominantly occurs in male and elderly patients and involves bilateral involvement of the adrenal glands, which frequently leads to adrenal insufficiency. Here, we review three recent cases of PAL at our hospital, and analyze data from our institution regarding patients with PAL from 2002 to 2014. On biochemical analysis, median levels of sIL2R (5027.5 U/mL) and LDH (1111.46 U/L) were elevated in Japanese PAL patients compared to other adrenal tumors. It is critical that clinicians be familiar with the traits of PAL, especially for its differential diagnosis from adrenal large tumors.
    No preview · Article · Nov 2014

  • No preview · Article · Oct 2014 · Cancer Research

  • No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Unlabelled: 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 cross-linking. Using exon array analysis and quantitative validation, LOXL2 was shown to be significantly upregulated in clinical specimens of human ccRCC tumor tissues, compared with adjacent noncancerous renal tissues, and this elevated expression correlated with the pathologic 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 α5 (ITGAV5) and β1 (ITGB1) via protease- and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin α5 correlated with the pathologic tumor grades. In conclusion, LOXL2 is a potent regulator of integrin α5 and integrin β1 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 α5 and β1.
    No preview · Article · Aug 2014 · Molecular Cancer Research
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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.
    Full-text · Article · Jul 2014 · The Prostate
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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.
    No preview · Article · Jun 2014 · Hinyokika kiyo. Acta urologica Japonica
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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.
    No preview · Article · Apr 2014 · International Journal of Clinical Oncology

Publication Stats

647 Citations
238.88 Total Impact Points

Institutions

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