Nobuo Shinohara

Outcome of Metastasectomy for Urothelial Carcinoma: A Multi-Institutional Retrospective Study in Japan

PURPOSEnWe determined prognostic factors associated with prolonged survival after metastasectomy for urothelial carcinoma.nnnMATERIALS AND METHODSnA total of 42 patients who underwent resection of urothelial carcinoma metastases with curative intent at 4 Japanese university hospitals were included in analysis. Of the patients 41 of 42 underwent systemic chemotherapy before and/or after metastasectomy. Overall survival was analyzed using the Kaplan-Meier method. The relationship between clinical characteristics and survival was analyzed using the log rank test.nnnRESULTSnMetastasectomy included lymph node dissection in 20 cases, pulmonary resection in 12, pelvic exenteration in 3, resection of local recurrence in 2, resection of subcutaneous metastasis in 2, liver resection in 1 and other in 2. Median overall survival was 29 months (IQR 19-80) from the initiation of treatment for metastases and 26 months (IQR 11-90) from metastasectomy. The overall 5-year survival rate after metastasectomy was 31%. On univariate analysis patients treated with metastasectomy for a solitary lung or solitary lymph node metastasis had significantly longer survival than the others who underwent metastasectomy (81 vs 19 months, log rank test p = 0.0296).nnnCONCLUSIONSnLong-term cancer control could be achieved in a subgroup of patients who undergo metastasectomy, especially those with a solitary lung or solitary lymph node metastasis.

Comparison of 90-day complications between ileal conduit and neobladder reconstruction after radical cystectomy: A retrospective multi-institutional study in Japan

To determine the differences in the type, incidence, and severity of 90‐day morbidity after radical cystectomy between two different methods of urinary diversion, ileal conduit and neobladder.

Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells

Targeting tumor angiogenesis is an established strategy for cancer therapy. Because angiogenesis is not limited to pathological conditions such as cancer, molecular markers that can distinguish between physiological and pathological angiogenesis are required to develop more effective and safer approaches for cancer treatment. To identify such molecules, we determined the gene expression profiles of murine tumor endothelial cells (mTEC) and murine normal endothelial cells using DNA microarray analysis followed by quantitative reverse transcription–polymerase chain reaction analysis. We identified 131 genes that were differentially upregulated in mTEC. Functional analysis using siRNA‐mediated gene silencing revealed five novel tumor endothelial cell markers that were involved in the proliferation or migration of mTEC. The expression of DEF6 and TMEM176B was upregulated in tumor vessels of human renal cell carcinoma specimens, suggesting that they are potential targets for antiangiogenic intervention for renal cell carcinoma. Comparative gene expression analysis revealed molecular differences between tumor endothelial cells and normal endothelial cells and identified novel tumor endothelial cell markers that may be exploited to target tumor angiogenesis for cancer treatment.

Identification and expression of troponin T, a new marker on the surface of cultured tumor endothelial cells by aptamer ligand

The identification of a specific biomarker involves the development of new clinical diagnostic tools, and an in‐depth understanding of the disease at the molecular level. When new blood vessels form in tumor cells, endothelial cell production is induced, a process that plays a key role in disease progression and metastasis to distinct organs for solid tumor types. The present study reports on the identification of a new biomarker on primary cultured mouse tumor endothelial cells (mTECs) using our recently developed high‐affinity DNA aptamer AraHH001 (Kd = 43 nmol/L) assisted proteomics approach. We applied a strategy involving aptamer‐facilitated biomarker discovery. Biotin‐tagged AraHH001 was incubated with lysates of mTECs and the aptamer‐proteins were then conjugated with streptavidin magnetic beads. Finally, the bound proteins were separated by sodiumdodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) with silver staining. We identified troponin T via matrix assisted laser desorption ionization‐time of flight (MALDI‐TOF) mass spectrometry, the molecular target of aptamer AraHH001, and its presence was confirmed by measuring mRNA, protein levels, western blot, immunostaining, a gel shift assay of AraHH001 with troponin T. We first report here on the discovery of troponin T on mTECs, a promising and interesting diagnostic tool in the development of antiangiogenic therapy techniques the involves the targeting of the tumor vasculature.

Adaptor protein CRK induces epithelial–mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop

We have previously reported that an adaptor protein CRK, including CRK‐I and CRK‐II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK‐I/‐II, but not CRK‐like, in human bladder cancer tissues compared to normal urothelium. We established CRK‐knockdown bladder cancer cells using 5637 and UM‐UC‐3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c‐Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor‐dependent and ‐independent manner. In epithelial–mesenchymal transition‐related molecules, E‐cadherin was upregulated by CRK elimination, whereas N‐cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c‐Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM‐UC‐3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c‐Met/CRK feedback loop for epithelial–mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.

RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass.

To evaluate the association between the RENAL nephrometry score and annual growth rates of renal masses presumed to be renal cell carcinoma.

Five-point Likert scaling on MRI predicts clinically significant prostate carcinoma

BackgroundTo clarify the relationship between the probability of prostate cancer scaled using a 5-point Likert system and the biological characteristics of corresponding tumor foci.MethodsThe present study involved 44 patients undergoing 3.0-Tesla multiparametric MRI before laparoscopic radical prostatectomy. Tracing based on pathological and MRI findings was performed. The relationship between the probability of cancer scaled using the 5-point Likert system and the biological characteristics of corresponding tumor foci was evaluated.ResultsA total of 102 tumor foci were identified histologically from the 44 specimens. Of the 102 tumors, 55 were assigned a score based on MRI findings (score 1: nu2009=u20093; score 2: nu2009=u20093; score 3: nu2009=u200916; score 4: nu2009=u200911 score 5: nu2009=u200922), while 47 were not pointed out on MRI. The tracing study revealed that the proportion of >0.5 cm3 tumors increased according to the upgrade of Likert scores (score 1 or 2: 33 %; score 3: 68.8 %; score 4 or 5: 90.9 %, χ2 test, pu2009<u20090.0001). The proportion with a Gleason score >7 also increased from scale 2 to scale 5 (scale 2: 0 %; scale 3: 56.3 %; scale 4: 72.7 %; 5: 90.9 %, χ2 test, pu2009=u20090.0001). On using score 3 or higher as the threshold of cancer detection on MRI, the detection rate markedly improved if the tumor volume exceeded 0.5 cm3 (<0.2 cm3: 10.3 %; 0.2-0.5 cm3: 25 %; 0.5-1.0 cm3: 66.7 %; 1.0u2009<u2009cm3: 92.1 %).ConclusionsEach Likert scale favobably reflected the corresponding tumor’s volume and Gleason score. Our observations show that “score 3 or higher” could be a useful threshold to predict clinically significant carcinoma when considering treatment options.

Clinical significance and therapeutic potential of prostate cancer antigen-1/ALKBH3 in human renal cell carcinoma.

Prostate cancer antigen-1 (PCA-1)/ALKBH3 has been recently identified in human prostate cancer and its expression is correlated with disease progression and prognosis. However, the precise role and function of PCA-1/ALKBH3 in human malignancies are largely unknown. In the present study, we investigated the clinical significance and therapeutic potential of PCA-1/ALKBH3 in renal cell carcinoma (RCC). PCA-1/ALKBH3 expression was examined by immunohistochemistry in 101 RCC patients who underwent radical or partial nephrectomy. Its expression was positively correlated with advanced pathological T- and M-factors and TNM stage (T, P<0.05; M, P<0.01; TNM, P<0.01, respectively). In the prognostic analysis, PCA-1/ALKBH3-negative patients with RCC had a significantly better prognosis than PCA-1/ALKBH3-positive patients (5-year survival rate, 92.9 vs. 75.9%, respectively; P<0.05). Next, the therapeutic potential of targeting PCA-1/ALKBH3 was further evaluated by small interfering RNA method using a human RCC cell line (CAKI-1). We found that PCA-1/ALKBH3 knockdown significantly inhibited the growth of CAKI-1 cells compared with the control (P<0.001). Furthermore, knockdown of PCA-1 induced apoptosis in CAKI-1 cells, as assessed by poly(ADP-ribose) polymerase-cleavage assays. We demonstrated for the first time that PCA-1/ALKBH3 expression has a significant prognostic impact on patient prognosis in RCC. Furthermore, its knockdown has a therapeutic efficacy on RCC. Taken together, both our clinical and experimental data strongly suggest that PCA-1/ALKBH3 may be functionally important and a novel molecular target for human RCC.

Role of cytoreductive nephrectomy for Japanese patients with primary renal cell carcinoma in the cytokine and targeted therapy era.

To assess the efficacy of cytoreductive nephrectomy for Japanese patients with primary metastatic renal cell carcinoma in the cytokine and targeted therapy era.

Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular‐targeted therapy

A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular‐targeted therapy and the clinical usefulness of the Japanese metastatic renal cancer (JMRC) prognostic classification. Of 389 consecutive patients for whom treatment was started between 2008 and 2010 at 23 hospitals in Japan, 357 patients who received vascular endothelial growth factor receptor‐tyrosine kinase inhibitor (VEGFR‐TKI) or cytokine as initial systemic therapy were the subject of the present study. Patients were classified into three prognostic groups according to the JMRC prognostic classification. The endpoints were progression‐free survival (PFS) and overall survival (OS) after the start of the initial treatment. The median PFS and OS for the entire cohort of 357 patients were 9.1 and 27.2 months, respectively. VEGFR‐TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone metastasis. The median PFS and OS were 11.0 and 23.2 months and 5.4 and 38.2 months in the VEGFR‐TKI group and the cytokines group, respectively. The JMRC prognostic classification was useful as a prognostic model for PFS and OS (c‐indexes: 0.613 and 0.630 in patients who initially received VEGFR‐TKI and 0.647 and 0.642 in patients who received cytokines, respectively). The present study showed for the first time the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular‐targeted therapy. The JMRC prognostic classification may be clinically useful as a prognostic model.