Kazutoshi Fujita

Osaka General Medical Center, Ōsaka, Ōsaka, Japan

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Publications (57)115.13 Total impact

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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 : MCR. 11/2014;
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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; · 4.35 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 : MCR. 08/2014;
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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: 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 05/2014; · 3.84 Impact Factor
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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; · 1.41 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; · 3.03 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; · 1.73 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; · 1.73 Impact Factor
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    ABSTRACT: Despite an increasing prevalence of patients with docetaxel refractory prostate cancer, little is known about the tumour biology of the docetaxel-resistant residual tumour cells compared with primary tumour cells. In this study, we demonstrated that the tumourigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines DRD, 1G7 and PC3DR cells compared with parental DU145 cells or PC3 cells. An enhanced tumourigenic potential was controlled by the c-Myc protein, which was stabilised by constitutively activated ERK1/2 in DRD, 1G7 and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was up-regulated in DRD, 1G7 and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilising c-Myc. Thus, docetaxel treatment may constitutively activate the CXCR4, ERK1/2 and c-Myc signalling loop in docetaxel-resistant residual prostate cancer cells. Furthermore, the constitutive CXCR4, ERK1/2 and c-Myc signalling activation was demonstrated in clinical cancerous tissue samples from human patients with docetaxel-resistant prostate cancer. In docetaxel-resistant residual prostate cancer cells, the enhanced tumourigenic potential was reduced by PD98059, an ERK1/2 inhibitor, or by AMD3100, a CXCR4 antagonist. Thus, these signalling pathways may become treatment targets for inhibiting aggressive residual tumour cells after chemotherapy.
    Molecular Cancer Research 06/2013; · 4.35 Impact Factor
  • AACR 104th Annual Meeting 2013, Washington, DC; 04/2013
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    ABSTRACT: We report a case of hyperuricemia and acute kidney injury associated with mizoribine (MZR). A 15- year-old male with congenital renal hypoplasia underwent kidney transplantation. We used tacrolimus extended release (0.15 mg/kg/day), mizoribine (MZR) (12 mg/kg/day), prednisolone and basiliximab as immunosuppressants. On the 35th post operative day, he complained of acute right chest pain, right inguinal pain and dyspnea. Serum uric acid and creatinine were elevated. Accordingly, we changed MZR to mycophenolate mofetil, and added allopurinol and potassium citrate. Gradually, the symptoms disappeared and renal function was improved. In this case, prolonged MZR metabolism, hyperuricemia and progressive renal dysfunction may have formed a vicious cycle. In conclusion, monitoring of serum uric acid level is necessary, especially when using a high dose MZR.
    Hinyokika kiyo. Acta urologica Japonica 02/2013; 59(2):103-6.
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    ABSTRACT: We report a case of urothelial carcinoma (UC) in a 69-year-old man that occurred after renal transplantation. He had started receiving hemodialysis therapy in 2004 due to diabetic nephropathy and underwent living related renal transplantation from his brother in 2005. He was referred to our hospital in May 2009 with asymptomatic microscopic hematuria. Cystoscopy findings revealed multiple bladder tumors, and transurethral resection of bladder tumor (TUR-BT) followed by intravesical instillation of pirarubicin was performed. Histopathological findings revealed UC (G1>G2, pTa). Cytology findings after the operation did not become negative; urine specimen from the native right ureter was positive, and abdominal computed tomography (CT) demonstrated a right pelvic tumor. In January 2010, a laparoscopic right nephroureterectomy was performed and pathological examination findings revealed UC in the right pelvis (G3>G2, INFβ, pT3). In March 2010, recurrence of the bladder tumor was demonstrated as carcinoma in situ (CIS) of the bladder and left native ureter. In June 2010, a radical cystectomy with left nephroureterectomy and ileal conduit diversion were performed. One week after that operation, laboratory results revealed abnormal hepatic function and CT showed multiple liver metastases. The patient died in August 2010, 2 months after surgery.
    Hinyokika kiyo. Acta urologica Japonica 02/2013; 59(2):117-20.
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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 01/2013; 8(9):e74313. · 3.53 Impact Factor
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    ABSTRACT: A 55-year-old woman who presented with a retroperitoneal tumor was referred to our department. At the age of 51, she underwent a total gastrectomy for gastric cancer. Postoperatively, TS-1 administration was given for Virchow lymph node metastasis, which disappeared within 2 years and TS-1 was stopped. However, computed tomography revealed a retroperitoneal tumor adjacent to the inferior vena cava, which gradually increased and began to compress the inferior vena cava. Under a diagnosis of retroperitoneal tumor, laparoscopic resection was performed. Pathological findings led to a diagnosis of lymph node metastasis from an adenocarcinoma of the stomach.
    Hinyokika kiyo. Acta urologica Japonica 12/2012; 58(12):683-686.
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    ABSTRACT: OBJECTIVES: To assess the impact of preoperative serum sodium concentration on the prognosis of patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy. METHODS: The clinical records of 139 patients treated for upper urinary tract urothelial carcinoma by nephroureterectomy were retrospectively reviewed. Recurrence-free and cancer-specific survival curves were calculated using the Kaplan-Meier method, with the difference between curves evaluated using the log-rank test. A multivariate analysis was carried out by Cox's proportional hazard model to identify prognostic factors. RESULTS: The median (range) follow-up time was 27 (1-139) months. The median (range) preoperative serum sodium was 141 (134-147) mEq/L. Five-year cancer-specific survival estimates for patients above and below the median preoperative serum sodium were 81.7% (95% confidence interval: 68.7-89.7) and 50.6% (95% confidence interval: 30.3-67.8), respectively. In the multivariate analysis, preoperative sodium concentration, pathological T stage, and lymphovascular invasion were independent and significant prognostic factors for cancer-specific survival. A prognostic model of risk classification for cancer-specific survival involving these parameters was developed, and 5-year cancer-specific survival estimates were 29.9% (95% confidence interval: 14.5-47.0) for the poor risk group (hazard ratio 19.95 [95% confidence interval: 8.5-46.6]; P < 0.001), 81.6% (95% confidence interval: 55.2-93.3) for the intermediate risk group (hazard ratio 5.70 [95% confidence interval: 1.27-25.5]; P = 0.022) and 97.9% (95% confidence interval 85.9-99.7) for the favorable risk group. CONCLUSION: These findings suggest for the first time that a low preoperative sodium level predicts a poor survival in upper urinary tract urothelial carcinoma patients treated by nephroureterectomy.
    International Journal of Urology 11/2012; · 1.73 Impact Factor
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    ABSTRACT: A 42-year-old woman presented with left renal tumor. Computed tomography showed a left renal tumor (6 cm in diameter) and a tumor thrombus at the left renal vein, which had equal density to fat tissue. She was diagnosed with malignant tumor, and underwent radical left nephrectomy and resection of thrombus. Pathological diagnosis was angiomyolipoma with no findings of malignancy. No signs of recurrence or metastasis have been observed for 8 months after the operation.
    Hinyokika kiyo. Acta urologica Japonica 05/2012; 58(5):227-9.
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with multiple neurofibroma and café-au-lait spots. We report a case of plexiform neurofibroma of the bladder associated with NF1. A 34-year-old female was referred to our hospital for thickness of the bladder wall. Multiple café-au-lait spots and neurofibroma was found on her skin,and she was diagnosed with neurofibromatosis type 1. Ultrasound examination demonstrated bladder wall thickening,and cystoscopy revealed an irregular and erythematous mucosa. Transurethral biopsy of the bladder wall was performed. Histopathological diagnosis was plexiform neurofibroma of the bladder.
    Hinyokika kiyo. Acta urologica Japonica 04/2012; 58(4):215-8.
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    ABSTRACT: Acute pyelonephritis (APN) is a common complication of ureteral obstruction caused by urolithiasis, and it can be lethal if it progresses to septic shock. We investigated the clinical characteristics of patients undergoing emergency drainage and assessed risk factors for septic shock. A retrospective study was performed of 98 patients (101 events) requiring emergency drainage at our urology department for obstructive APN associated with upper urinary tract calculi from January 2003 to January 2011. Clinical characteristics were summarized, and risk factors for septic shock were assessed by logistic regression analysis. Objective evidence of sepsis was found in 64 (63.4%) events, and 21 events (20.8%) were categorized as septic shock. Ninety-six patients recovered, but 2 patients died of septic shock. Multivariate analysis revealed that age and the presence of paralysis were independent risk factors for septic shock. APN associated with upper urinary tract calculi is a severe disease that should be treated with caution, particularly when risk factors are present.
    BMC Urology 03/2012; 12:4. · 1.69 Impact Factor

Publication Stats

364 Citations
115.13 Total Impact Points

Institutions

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