BACKGROUND/AIM:Evaluation of long-term outcomes is essential for the successful treatment of localized prostate cancer; however, the risk of late recurrence following brachytherapy is still not clear. This study aimed to evaluate the long-term outcomes of low-dose-rate brachytherapy (LDR-BT) for localized prostate cancer in Japanese patients and identify factors associated with late recurrence after treatment.PATIENTS AND METHODS:This single-center, cohort study included patients who underwent LDR-BT at the Tokushima University Hospital in Japan between July 2004 and January 2015; 418 patients, who were followed-up at least 7 years after LDR-BT, were included in the study. Biochemical progression free survival (bPFS) was defined according to the Phoenix definition (nadir PSA+2 ng/ml) and bPFS and cancer specific survival (CSS) were calculated using Kaplan-Meier survival curves. Univariate and multivariate analyses were performed using Cox proportional hazard regression models.RESULTS:Approximately half of the patients with PSA >0.5 ng/ml at 5 years after LDR-BT had a recurrence within the next 2 years. However, only 1.4% of the patients with a PSA ≤0.2 ng/ml at 5 years post-treatment showed tumor recurrence, including those at high risk of treatment failure according to the D'Amico classification. In multivariate analysis, PSA level at 5 years post-treatment was the only predictor of late recurrence after 7 years of treatment.CONCLUSION:PSA levels at 5 years post-treatment were associated with long-term recurrence of localized prostate cancer, which can help alleviate patient anxiety concerning prostate cancer recurrence if PSA levels remain low at 5 years after LDR-BT.

BACKGROUND/AIM:Intermediate-risk prostate cancer (PCa) is a highly heterogeneous disease. Although low-dose-rate brachytherapy (LDR-BT) is mainly used for low- to intermediate-risk PCa, limited reports have evaluated the detailed differences in outcomes, including differences between patients with ISUP grade group (GG) 2 and GG3 intermediate-risk PCa. This study aimed to investigate the differences in outcomes between intermediate-risk Japanese patients with GG2 and GG3 PCa who underwent LDR-BT.PATIENTS AND METHODS:This single-center retrospective study included 342 consecutive patients with intermediate-risk PCa; 232 patients with GG2 and 110 with GG3 were treated with LDR-BT at Tokushima University Hospital between July 2004 and December 2019.RESULTS:No significant difference in 5-year biochemical progression-free survival and cancer-specific survival was observed between patients with GG2 and those with GG3 (p=0.649 and p=0.633, respectively). Multivariate analysis showed that radiation doses up to 90% of the prostate volume (D90) and the percentage of positive cores were predictors of recurrence in all patients with intermediate-risk PCa. Group analyses showed that D90 was a predictor for recurrence in patients with GG2. In contrast, a high percentage of positive cores was a significant risk factor for recurrence in patients with GG3.CONCLUSION:Positive core ratios observed on prostate biopsy correlated with higher recurrence rates after LDR-BT. This indicates that the proportion of positive cores in the biopsy may be an important factor in predicting the likelihood of recurrence, especially for patients with GG3 PCa.

BACKGROUND More patients with renal cell carcinoma are now diagnosed with the disease in its early stages. Although patients with pT1a renal cell carcinoma have a good prognosis and low recurrence rate, a few patients still experience recurrence. Herein, we evaluated the clinicopathological risk factors for postoperative recurrence of pT1aN0M0 renal cell carcinoma. METHODS An renal cell carcinoma survey was conducted by the Japanese Urological Association to register newly diagnosed cases of renal cell carcinoma. A total of 1418 patients diagnosed with pT1aN0M0 renal cell carcinoma who underwent surgery as the primary surgical treatment were included. We analyzed the recurrence-free survival using the Kaplan-Meier method and clinicopathological factors for recurrence using Cox proportional hazards models. RESULTS Among 1418 patients, 58 (4.1%) had recurrences after a median follow-up of 62.8 months. The median time to recurrence was 31.0 months. Metastases to the lungs and the bone were observed in 20 and 10 cases, respectively. Significant differences in sex, tumor size, Eastern Cooperative Oncology Group performance status, and dialysis history, preoperative hemoglobin levels, C-reactive protein levels and creatinine levels were observed between the recurrence and non-recurrence groups. Multivariate analysis identified male sex, high C-reactive protein level and tumor size ≥3 cm as independent risk factors. The 5-year recurrence-free survival of patients with 0, 1, 2 and 3 risk factors was 99.0, 97.2, 93.1 and 80.7%, respectively. CONCLUSIONS Male sex, tumor diameter and a high C-reactive protein level were independent recurrence risk factors for pT1a renal cell carcinoma; special attention should be paid to patients with these risk factors during postoperative follow-up.

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (MP81)1 Apr 2019MP81-12 GALECTIN-3 IS INVOLVED IN THE TUMOR PROGRESSION AND DRUG RESISTANCE INDUCED BY TAXANE CHEMOTHERAPY AND POLY(ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR IN CASTRATION-RESISTANT PROSTATE CANCER Tomoharu Fukumori*, Kei Daizumoto, Megumi Tsuda, Keisuke Ozaki, Yoshito Kusuhara, Hidehisa Mori, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Masayuki Takahashi, and Hiro-omi Kanayama Tomoharu Fukumori*Tomoharu Fukumori* More articles by this author , Kei DaizumotoKei Daizumoto More articles by this author , Megumi TsudaMegumi Tsuda More articles by this author , Keisuke OzakiKeisuke Ozaki More articles by this author , Yoshito KusuharaYoshito Kusuhara More articles by this author , Hidehisa MoriHidehisa Mori More articles by this author , Tomoya FukawaTomoya Fukawa More articles by this author , Yasuyo YamamotoYasuyo Yamamoto More articles by this author , Kunihisa YamaguchiKunihisa Yamaguchi More articles by this author , Masayuki TakahashiMasayuki Takahashi More articles by this author , and Hiro-omi KanayamaHiro-omi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557431.95453.0bAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Castration-resistant prostate cancer (CRPC) has been leading cause of prostate cancer-related death at present. Therefore, improved therapeutic options are needed for men with CRPC and the mechanism of tumor progression and drug resistance should be elucidated. We have found that galectin-3 enhances anti-cancer drug resistance induced by cisplatin or etoposide through the regulation of caspase signaling in prostate cancer. Here, we investigate the effects of galectin-3 for taxane chemotherapy and new promising drug PARP inhibitor in CRPC. We also investigate the tumor progression and drug resistance mechanisms of galectin-3 for CRPC using bioinformatics analysis. METHODS: LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3), or PC-3 and galectin-3-knockdown PC-3 (PC3-siGal-3) cells were cultured with androgen-depleted media with 5% charcoal-stripped serum. Cells were treated for 24 hours with mock, docetaxel (1 nM), and olaparib (10 μM). Apoptotic cells were measured by propidium iodide permeability and annexin V binding by FACScan. Gene profile was analyzed by microarray analysis and mRNA expression was confirmed by quantitative PCR. We have combined the bioinformatics analysis using DAVID to assess the galectin-3-induced molecules and pathways for cancer progression. RESULTS: Galectin-3 significantly suppressed cell apoptosis induced by 1 nM docetaxel or 10 μM olaparib in LNCaP (percent of apoptotic cells in docetaxel: LNCaP 17.4% vs LNCaP-Gal-3 6.8%, olaparib: LNCaP 24.2% vs LNCaP-Gal-3 8.9%, respectively) through the regulation of PI3K and caspase signaling. Based on bioinformatics analysis, galectin-3 expressing cells significantly enhanced PI3K-Akt signaling pathway, rap1 signaling pathway, and TGF-beta signaling pathway by 5 times or more. In LNCaP-Gal-3 and PC-3 cells, galectin-3 upregulated the cell surviving factors such as PI3K and Akt, cell growth factors such as EGF and TGF-beta, bone metastasis-related genes such as RUNK2 and BMP7, and PARP-related genes such as PARP14 which promote survival of cancer cells in agreement with the results of bioinformatics analysis. CONCLUSIONS: The results indicate that galectin-3 is involved in the tumor progression and drug resistance in CRPC by regulating cell surviving signal, cell growth factors, and PARP-related genes. These results suggest that galectin-3 is one of the target molecules for future treatments in patients with CRPC. Source of Funding: none Tokushima, Japan© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e1176-e1176 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tomoharu Fukumori* More articles by this author Kei Daizumoto More articles by this author Megumi Tsuda More articles by this author Keisuke Ozaki More articles by this author Yoshito Kusuhara More articles by this author Hidehisa Mori More articles by this author Tomoya Fukawa More articles by this author Yasuyo Yamamoto More articles by this author Kunihisa Yamaguchi More articles by this author Masayuki Takahashi More articles by this author Hiro-omi Kanayama More articles by this author Expand All Advertisement PDF downloadLoading ...

592 Background: Previously we have identified the prognostic gene set of ccRCC patients, where insulin receptor (INSR) expression was decreased in the patients with poor outcome (Proc Natl Acad Sci U S A., 2001). We examined the clinical significance of decreased INSR expression and sought to elucidate the underlying mechanisms. Methods: The INSR expression was immunohistochemically examined in the nephrectomy specimens of RCC patients (n = 33) who then received axitinib. We established patient derived Xenograft model (PDX) of ccRCC and examined the INSR expression in the axitinib resistant PDX tumors by Western blotting. As the INSR is expressed in the vascular endothelial cells, we co-cultured the RCC cell lines with the human renal glomerular endothelial cells (HGEC) treated with si-RNA of INSR (si-INSR) and the microarray experiment was conducted. Results: In RCC patients with axitinib, those with low INSR expression had poor outcome (median PFS 19.5 vs 2.3 months, p < 0.001; median OS 34.2 vs 5.6 months, p = 0.001). The INSR expression was the significantly independent predictor of PFS (p = 0.006). In the axitinib-resistant PDX tumors, the expression of INSR was decreased. In the co-culture experiments, the microarray experiments revealed that the decreased INSR expression in the HGECs may be involved with the important signaling pathway including interferon response in Caki-1 cells. Interferon- β was highly expressed in HGECs with si-INSR. The decreased INSR expression and the increased interferon-β expression in HGEC were confirmed when axitinib was administered. The Caki-1 cells that was co-cultured with HGECs treated with si-INSR demonstrated high expression of PD-L1. The PD-L1 expression was increased in a concentration-dependent manner of recombinant interferon-β and increased phosphorylation of STAT1 and STAT3 were observed. Conclusions: In conclusion, the decreased INSR expression could be a biomarker to predict the resistance to VEGFR-TKIs. The decreased INSR expression was correlated with the increased interferon-β expression in HGECs, which leads to the induction of PD-L1 through increased phosphorylation of STAT1 and STAT3.

Objectives: Perinephric fat invasion (PFI) of renal cell carcinoma (RCC) is known to be associated with adverse pathological features and poor prognosis. We analyzed these associations using a sub-group of the RCC registry of The Cancer Registration Committee of the Japanese Urological Association. Methods: The study cohort of 2998 non-metastatic cases was retrieved from RCC registry (3648 in total). We compared clinicopathological characteristics of cases with PFI (n = 256) and without PFI (n = 2742), and investigated the impact of PFI on cancer-specific survival using univariate and multivariate analyses. Results: Compared with non-PFI cases, PFI cases were older (P = 0.003), and more likely to be hypertensive (P = 0.034) and symptomatic at presentation (P < 0.001). PFI tumors were larger (P < 0.001), and more often have sarcomatoid component (P < 0.001) and tumor thrombus (P < 0.001). Cancer-specific survival was significantly shorter in cases with PFI than without (P < 0.001). The difference in survival tended to be greater in cases with large tumors but was significant in small tumor sub-groups. Cancer-specific survival was significantly shorter in cases with both PFI and renal vein involvement (RVI) in comparison to those with PFI or RVI alone (P = 0.011, P = 0.007, respectively). On multivariate analysis PFI with and without sinus fat invasion remained as an independent risk factor along with symptom at presentation, low body mass index, hypertension, multiple tumors, large tumor size (>7.0 cm), sarcomatoid component and RVI. Conclusions: PFI was associated with advanced age and aggressive pathological features. PFI is an independent prognostic factor in non-metastatic RCC.

Background/Aim: The aim of this study was to elucidate the relationship between the progression of bladder cancer (BCa) and TLR4 expression. Materials and Methods: The relationship between TLR4 expression and prognosis of BCa patients was analyzed using a publicly available database and immunohistochemical staining of clinical samples. The effect of TLR4 knockdown was also examined on the invasive capabilities of BCa cells. Finally, to investigate the biological function of TLR4, the gene expression profile of TLR4-depleted BCa cells was analyzed by microarray analysis. Results: Expression of TLR4 was inversely associated with prognosis of patients with invasive BCa, and depletion of TLR4 significantly enhanced the invasive capability of BCa cells. Gene expression profiling revealed that depletion of TLR4 led to high expression of epithelial differentiation genes. Furthermore, expression of TLR4 was found to be extremely low in areas of squamous differentiation. Conclusion: Low TLR4 expression was correlated with tumor progression.

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2018MP45-17 GALECTIN-3 PLAYS CRITICAL ROLES FOR THE GROWTH OF BENIGN PROSTATIC HYPERPLASIA Kei Daizumoto, Yayoi Fukuhara, Keisuke Ozaki, Yoshito Kusuhara, Hidehisa Mori, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Tomoharu Fukumori, Masayuki Takahashi, and Hiro-omi Kanayama Kei DaizumotoKei Daizumoto More articles by this author , Yayoi FukuharaYayoi Fukuhara More articles by this author , Keisuke OzakiKeisuke Ozaki More articles by this author , Yoshito KusuharaYoshito Kusuhara More articles by this author , Hidehisa MoriHidehisa Mori More articles by this author , Tomoya FukawaTomoya Fukawa More articles by this author , Yasuyo YamamotoYasuyo Yamamoto More articles by this author , Kunihisa YamaguchiKunihisa Yamaguchi More articles by this author , Tomoharu FukumoriTomoharu Fukumori More articles by this author , Masayuki TakahashiMasayuki Takahashi More articles by this author , and Hiro-omi KanayamaHiro-omi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1456AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Galectin-3, a multifunctional oncogenic protein, has been reported to play important roles of progression in a variety of cancer including prostate cancer through the regulation of cancer cell proliferation, apoptosis, invasion and metastasis. However, we also identified the frequent up-regulation of Galectin-3 in benign prostatic hyperplasia (BPH), yet its pathophysiological roles in BPH. Here, we report the involvement of Galectin-3 in the growth of BPH. METHODS To investigate the association of Galectin-3 expression and prostate volume, we examined serum Galectin-3 (pg/ml) with ELISA method in non-cancer cohort and analyzed the correlation between Galectin-3 expression and prostate volume with Speaman's correlation coefficient. Next, to analyzed proliferation abilities and the effect of Galectin-3 on smooth muscle, we examined knockdown of Galectin-3 expression by siRNA in BPH1 cells (benign prostatic hyperplasia cell line) and a co-culture experiment of BPH1 and PrSMC (Normal Human Prostate Smooth Muscle. Cells). Moreover, to investigate biological function of Galectin-3, we examined the gene expression profiles in Galectin-3-depleted BPH1 cells with microarray and bioinformatics analyses. RESULTS Correlation analysis revealed that serum Galectin-3 (ng/ml) were correlated with prostate volume (R=0.643 p=0.023) (Figure 1). Next, depletion of Galectin-3 suppressed cell proliferation in BPH1 cells. Moreover, depletion of Galectin-3 in BPH1 cells suppressed cell proliferation of PrSMC cells in a co-culture method, suggesting Galectin-3 enhanced proliferation of PrSMC cells. Bioinformatics analysis with GSEA revealed that depletion of Galectin-3 was involved in interferon a response and interferon a response and interferon ? response (FDR q value < 0.001) (Figure 2), suggesting Galectin-3 regulates the proliferation of PrSMC through interferon response. CONCLUSIONS Our findings suggest that Galectin-3 is significantly involved in the growth of BPH and a promising therapeutic target for patients with BPH. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e604 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kei Daizumoto More articles by this author Yayoi Fukuhara More articles by this author Keisuke Ozaki More articles by this author Yoshito Kusuhara More articles by this author Hidehisa Mori More articles by this author Tomoya Fukawa More articles by this author Yasuyo Yamamoto More articles by this author Kunihisa Yamaguchi More articles by this author Tomoharu Fukumori More articles by this author Masayuki Takahashi More articles by this author Hiro-omi Kanayama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

We report a case of left renal angiomyolipoma extending into the renal vein. A 67-year-old woman showed a left renal tumor which was 6 cm in diameter and had density equal to fat tissue in computed tomography. We suspected liposarcoma and performed radical nephrectomy and resection of thrombus. The pathological diagnosis was angiomyolipoma with no malignancy. To our knowledge, renal angiomyolipoma with tumor thrombus has been reported in 62 cases, and pulmonary embolism developed in 9 of these cases. We conclude that surgical treatment is effective in treating angiomyolipoma with tumor thrombus.

INTRODUCTION AND OBJECTIVES: We previously reported that International Prostate Symptom Scores (IPSS) resolution was useful indicator regarding prolonged urination disorder after low dose rate prostate brachytherapy (LDR-PBT).However, there is variety of definitions for IPSS resolution and the interpretation is also various.So, we reexamined the definition of IPSS resolution considering QOL status.METHODS: Between July 2004 and November 2017, 675 patients received LDR-PBT at our institution and were followed up at least 2 years.Prostate Specific Antigen (PSA), IPSS and QOL Scores were assessed pre-implant as well as at 1, 3, and 6 months after seed implantation, and every 6 months thereafter.IPSS resolution was defined as follows, definition 1: IPSS recovery to baseline score +0, definition 2: IPSS recovery to baseline score +1 and definition 3: IPSS recovery to baseline score +2.We also assessed correlation of IPSS resolution and QOL scores in accordance with each definition, and selected the most appropriate one.Using logistic-regression analyses, we also evaluated clinical factors with potential to delay IPSS resolution, which was most related to QOL Scores, including age, pretreatment IPSS, clinical stage, androgen deprivation therapy (ADT), prostate volume (PV), radiation dose to 90% of prostate volume (D90), and radiation dose to 30% of the urethral volume (UD30).RESULTS: In definition 1, IPSS resolution rate recovered from 11.5% to 51.0% during a time period from 1 month to 36 months after seed implantation.In definition 2, IPSS resolution rate recovered from 16.0% to 58.1% during the same periods and in definition 3, IPSS resolution rate recovered from 22.0% to 66.0% (Table 1).In follow-up after seed implantation, it was definition 3 that QOL recovery adapted to IPSS resolution most closely (Table 2).In definition 3, baseline IPSS more than 8 points (p<0.001) and D90 more than 160 Gy (p<0.001) were significant predictors for delayed IPSS resolution on multivariate analysis.CONCLUSIONS: Baseline IPSS+2 is the most appropriate definition of IPSS resolution which correlates most closely with QOL recovery after prostate brachytherapy.In this definition, higher baseline IPSS and higher D90 were predictors for prolonged urination disorder.

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2018MP58-17 THE CONTRIBUTION OF HGF-MET-MMP1 SIGNALING IN BLADDER CANCER INVASION, AND MET INHIBITOR AS A POTENTIAL THERAPEUTIC OPTION FOR INVASIVE BLADDER CANCER Tomoya Fukawa, Kei Daizumoto, Tomoharu Fukumori, Masayuki Takahashi, and Hiro-omi Kanayama Tomoya FukawaTomoya Fukawa More articles by this author , Kei DaizumotoKei Daizumoto More articles by this author , Tomoharu FukumoriTomoharu Fukumori More articles by this author , Masayuki TakahashiMasayuki Takahashi More articles by this author , and Hiro-omi KanayamaHiro-omi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1849AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Muscle-invasive bladder cancer (MIBC) has an especially poor prognosis, and clarification of the mechanism of MIBC invasion is urgent to discover appropriate treatment strategies and to improve the prognosis of patients with MIBC. Our previous report showed that co-culture of bladder cancer cells with mesenchymal cells which highly expressed HGF stimulated the invasion ability of bladder cancer cells. The aim of this study was to elucidate the underlying mechanisms of the increased invasion ability of bladder cancer cells by co-culture with mesenchymal cells, clarify the contribution of HGF-MET signaling pathway to bladder cancer progression and find a new therapeutic option for MIBC. METHODS We analyzed the expression of MET in the bladder cancer cell lines by Western blotting. Using the cell lines which highly expressed MET, we examined the effects of Cabozantinib on their proliferation and invasion abilities by using MTT and Matrigel invasion assays. To investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles of bladder cancer cells that were cultivated with/without the effects of the MET inhibitor, Cabozantinib (XL184). We also examined the effects of MMP-1 depletion on invasion ability to clarify the importance of HGF-MET-MMP1 signaling in bladder cancer invasion. To verify our results with clinical samples, we checked the relationship between the expression of MET and MMP-1 by using TCGA data. RESULTS The expression of MET was high in four of five bladder cancer cell lines, and 5637 and T24 cells showed especially high protein expression of MET. The treatment with HGF stimulated cell proliferation and invasion of these cancer cells, whereas Cabozantinib inhibited those effects induced by HGF stimulation. To clarify the underlying mechanisms, we analyzed gene expression profiles by using microarray and revealed that the expression of MMP-1 was significantly elevated by HGF addition. We also confirmed that Cabozantinib suppressed the expression of MMP-1 which was induced by HGF addition in bladder cancer cells. Consistent with these results, we found the strong association between the expression of MET and MMP1 by using TCGA data. Furthermore, the depletion of MMP-1 dramatically suppressed the invasion ability of bladder cancer cells, suggesting that HGF contributes bladder cancer invasion by regulating the expressions of MMP-1 CONCLUSIONS The results of this study suggested that the blockade of HGF-MET-MMP1 signaling could be a potential therapeutic option and Cabozantinib is one of the potential molecules for the treatment of MIBC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e779 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Tomoya Fukawa More articles by this author Kei Daizumoto More articles by this author Tomoharu Fukumori More articles by this author Masayuki Takahashi More articles by this author Hiro-omi Kanayama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II1 Apr 2018MP72-06 CORRELATION OF THE INSULIN RECEPTOR EXPRESSION AND THE RESISTANCE TO VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS IN ADVANCED CLEAR CELL RENAL CELL CARCINOMA Masayuki Takahashi, Kei Daizumoto, Yayoi Fukuhara, Keisuke Ozaki, Megumi Tsuda, Yoshito Kusuhara, Hidehisa Mori, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Tomoharu Fukumori, and Hiroomi Kanayama Masayuki TakahashiMasayuki Takahashi More articles by this author , Kei DaizumotoKei Daizumoto More articles by this author , Yayoi FukuharaYayoi Fukuhara More articles by this author , Keisuke OzakiKeisuke Ozaki More articles by this author , Megumi TsudaMegumi Tsuda More articles by this author , Yoshito KusuharaYoshito Kusuhara More articles by this author , Hidehisa MoriHidehisa Mori More articles by this author , Tomoya FukawaTomoya Fukawa More articles by this author , Yasuyo YamamotoYasuyo Yamamoto More articles by this author , Kunihisa YamaguchiKunihisa Yamaguchi More articles by this author , Tomoharu FukumoriTomoharu Fukumori More articles by this author , and Hiroomi KanayamaHiroomi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2290AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) demonstrate the significant efficacy for advanced clear cell renal cell carcinoma (ccRCC), however, it eventually becomes resistant to VEGFR-TKIs during the treatment. So far, the mechanisms for the resistance to VEGFR-TKIs remain to be fully elucidated. Previously we have identified the gene set which could predict poor prognosis of ccRCC patients (Takahashi M et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001). We examined whether the insulin receptor (INSR) expression in the gene set may correlate with the resistance to VEGFR-TKIs. METHODS The INSR expression was examined immunohistochemically in the nephrectomy specimens of the RCC patients (n=33) who then received axitinib as the VEGFR-TKI and correlated with their survival outcome. We compared the INSR expression of the nephrectomy or metastasectomy specimens before and after the administration of VEGFR-TKIs in 5 cases. The INSR expression of the human renal glomerular endothelial cells (HGEC) was compared before and after the administration of axitinib by Western blotting. In addition, we established patient derived Xenograft model (PDX) of ccRCC. Tumors of PDX were resected when it regrew and showed the resistance for axitinib and the INSR expression was compared before and after the treatment by Western blotting. RESULTS The INSR was expressed at the vessels surrounding tumor cells. Progression-free survival (PFS) was significantly shorter in the INSR-negative group than in the INSR-positive group. Multivariate analysis revealed that the INSR expression was the significantly independent predictor of PFS. In the specimens resected after VEGFR-TKI, the INSR expression was more frequently decreased. As the concentration of axitinib increased, the INSR expression in the HGEC was decreased. The tumors of PDX that were resected after demonstrating the resistance to axitinib had the decreased INSR expression. CONCLUSIONS The decreased INSR expression could be correlated with the resistance to VEGFR-TKI and its expression may be useful in selecting appropriate drugs for advanced ccRCC patients. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e954 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Masayuki Takahashi More articles by this author Kei Daizumoto More articles by this author Yayoi Fukuhara More articles by this author Keisuke Ozaki More articles by this author Megumi Tsuda More articles by this author Yoshito Kusuhara More articles by this author Hidehisa Mori More articles by this author Tomoya Fukawa More articles by this author Yasuyo Yamamoto More articles by this author Kunihisa Yamaguchi More articles by this author Tomoharu Fukumori More articles by this author Hiroomi Kanayama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...