Nobuo Shinohara - Academia.edu (original) (raw)

Papers by Nobuo Shinohara

International Journal of Oncology, 2010

Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts a... more Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts as a growth factor in several types of cancer cells. Our previous study revealed that an AM antagonist (AMA) suppressed the growth of pancreatic tumors in mice, although its mechanism was not elucidated. In this study, we constructed an AMA expression vector and used it to treat renal cell carcinoma (RCC) in mice. This AMA expression vector significantly reduced tumor growth in mice. In addition, microvessel density was decreased in AMA-treated tumors. To analyze the effect of AMA on tumor angiogenesis in this model, tumor endothelial cells (TECs) were isolated from RCC xenografts. TEC proliferation was stimulated by AM and it was inhibited by AMA significantly. AM induced migration of TECs and it was also blocked by AMA. However, normal ECs (NECs) were not affected by either AM or AMA. These results demonstrate that AMA has inhibitory effects on TECs specifically, not on NEC, thereby inhibiting tumor angiogenesis. Furthermore, we showed that vascular endothelial growth factor-induced mobilization of endothelial progenitor cell (EPC) into circulation was inhibited by AMA. These results suggest that AMA can be considered a good anti-angiogenic reagent that selectively targets TECs and EPC in renal cancer.

Cancer Science, 2017

Tumor blood vessels play an important role in tumor progression and metastasis. We previously rep... more Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH high TEC). ALDH high TEC have proangiogenic properties compared with ALDH low TEC. However, the association between ALDH high TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor-conditioned medium (tumor CM). The ALDH high population increased along with upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVEC. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDH high TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDH high TEC showed a higher grade of aneuploidy compared with that in ALDH low TEC. These results suggested that tumor-secreting factor increases ALDH high TEC populations that are resistant to 5-FU. Therefore, ALDH high TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.

PloS one, 2017

B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subs... more B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function, thus potentially regulating the immune response. In this study, we investigated the immune-regulatory roles of murine B cell subsets as regulatory APCs targeting alloreactive T cells. Either splenic B cells, peritoneal cavity (PerC) B cells, or non-B cells from Balb/c mice were intravenously injected into B6 mice. Serum levels of anti-Balb/c antibodies in the recipients of PerC B cells were significantly lower than those in the recipients of splenic B cells and PerC non-B cells, as determined over a 4-week period after the injection. Mixed-lymphocyte reaction (MLR) assays using splenocytes from the B6 mice at 2 weeks after the injection revealed the significantly reduced anti-Balb/c T cell-responses in the recipients of PerC B cells, as compared to those in the recipients of splenic B cell...

Cancer science, Jan 7, 2017

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rat... more Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6 months in treatment-naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and updated safety in 44 Japanese patients and compared with 169 non-Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first-line metastatic RCC were explored using a Cox proportional hazard model in all patients. With median follow-up of 33 months, fewer than half (16 of 44) of Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9 months (95% CI, 28.9-42.7). Estimated 1-, 2-, and 3-year survival probability (95% CI) was 86.4% (76.2-96.5), 75.0% (62.2-87.8), and 68.2% (54.4-81.9), respectively, in Japanese pati...

Scientific reports, Jan 4, 2016

In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, a... more In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell line...

Japanese journal of clinical oncology, Jan 29, 2016

To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and... more To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, ...

The Journal of Urology, 2016

INTRODUCTION AND OBJECTIVES: The oncologic benefit of retroperitoneal lymph node dissection (LND)... more INTRODUCTION AND OBJECTIVES: The oncologic benefit of retroperitoneal lymph node dissection (LND) for patients undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC) has not been established. We investigated the association of LND with oncologic outcomes among patients undergoing CN. METHODS: We identified 305 patients treated with CN for M1 RCC between 1990 and 2010, of whom 188 (62%) underwent LND. A propensity score (PS) for receipt of LND was estimated using clinicopathologic features. The associations of LND with cancer-specific (CSM) and all-cause mortality (ACM) were evaluated using Cox regression models and several PS techniques including stratification by PS quintile, adjustment for PS quintile, and inverse probability weighting (IPW). Internally predicted probabilities for pN1 disease were estimated using logistic regression. RESULTS: Overall, 74 (24%) patients were pN1. After PS adjustment, there were no significant differences in clinicopathologic features according to receipt of LND. Median follow-up among survivors was 8.5 years, during which time 284 patients died, including 274 from RCC. In the overall cohort, LND was not significantly associated with CSM or ACM using any of the PS techniques (Table). We further examined whether LND was associated with survival outcomes among patients at increased risk of pN1 disease. Among patients with radiographically enlarged nodes (cN1), LND was not significantly associated with CSM or ACM. Moreover, across increasing threshold probabilities for pN1 disease of 20%, 40%, 60%, or 80%, LND was not associated with reduced CSM or ACM. CONCLUSIONS: Among patients undergoing CN for metastatic RCC, LND was not associated with improved oncologic outcomes in the overall cohort, for patients with radiographic cN1 disease, or across increasing probability thresholds for pN1 disease. These findings suggest that LND at the time of CN does not confer an oncologic benefit by cytoreduction of nodal metastases.

The Japanese Journal of Urology, 1995

BioMed Research International, 2015

Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carci... more Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC) and to identify prognostic factors. Methods. A single center retrospective study of 96 patients with mRCC from December 2004 to August 2013. Results. The median follow-up time was 45 months. Thirty-one (32.3%) of the patients received complete resection of metastatic sites, 11 (11.5%) of the patients underwent incomplete resection of metastatic sites, and 54 (56.3%) of the patients received no surgery. In the univariate Kaplan-Meier analysis, the median overall survival times of the three groups were 52 months, 16 months, and 22 months, respectively (p<0.001). The difference in the overall survival time was statistically significant between complete resection and no surgery groups (HR = 0.43, p=0.009), while there was no significant difference between the incomplete metastasectomy and no surgery groups (HR = 1.80, p=0.102). According to the multivariate Cox regression anal...

The New England journal of medicine, Jan 25, 2015

Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encou... more Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1...

Cancer science, Jan 25, 2015

A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with ... more 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-tyrosine kinase inhibitor (VEGF-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. VEGF-TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone me...

Cancer science, 2014

In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metast... more In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty-four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6-49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7-64.2); the median duration of response, 11.1 months (95% CI, 8.2-13.7); and the median progression-free survival was 11.0 months (95% CI, 9.2-12.0), assessed by the independent review committee. Common treatment-related all-grade adverse events were hypertension (88%), hand-foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and d...

BMC research notes, Jan 15, 2015

BackgroundRenal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clin... more BackgroundRenal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features.Case presentationA 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular ma...

PloS one, 2014

Tumor blood vessels play an important role in tumor progression and metastasis. It has been repor... more Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-...

Cancer science, 2014

Recent studies have reported that stromal cells contribute to tumor progression. We previously de... more Recent studies have reported that stromal cells contribute to tumor progression. We previously demonstrated that tumor endothelial cells (TEC) characteristics were different from those of normal endothelial cells (NEC). Furthermore, we performed gene profile analysis in TEC and NEC, revealing that suprabasin (SBSN) was upregulated in TEC compared with NEC. However, its role in TEC is still unknown. Here we showed that SBSN expression was higher in isolated human and mouse TEC than in NEC. SBSN knockdown inhibited the migration and tube formation ability of TEC. We also showed that the AKT pathway was a downstream factor of SBSN. These findings suggest that SBSN is involved in the angiogenic potential of TEC and may be a novel TEC marker.

Cancer science, Jan 28, 2015

We have previously reported that an adaptor protein CRK including CRK-I and CRK-II plays essentia... more 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 validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with a marked invasion, caused of distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry demonstrated a striking enhancement of CRK-I/-II, but not CRK-L, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which exhibited 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 HGF-dependent and -independent manner. In epithelial-mesenchymal transition (EMT)-related molecules, E-cadherin was up-regul...

Urologia Internationalis, 2011

Adult-onset Xp11.2 translocation renal cell carcinoma is a rare malignancy that has an aggressive... more Adult-onset Xp11.2 translocation renal cell carcinoma is a rare malignancy that has an aggressive clinical course and poor prognosis. The reasons for this include the fact that most patients have an advanced clinical stage at diagnosis and also that there is a lack of effective systemic therapy. We herein present the case of a 32-year-old woman suffering from node-positive Xp11.2 translocation renal cell carcinoma who underwent radical nephrectomy with an extensive retroperitoneal lymph node dissection, followed by two times of surgical resection for recurrent nodal disease. The patient has experienced no recurrent disease 4.5 years after the last operation and remains free of disease. Surgical approach to recurrent disease, if the recurrent site can be judged to be limited, might be one of the feasible treatment options in patients with Xp11.2 translocation renal cell carcinoma.

Journal of Clinical Oncology, 2010

Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 ... more Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). Methods Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. Results A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-fre...

Japanese Journal of Clinical Oncology, 2009

This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastat... more This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). Methods: Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECISTdefined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. Results: In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). Conclusions: In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.

Japanese Journal of Clinical Oncology, 2012

We reviewed the outcomes of metastatic renal cell carcinoma patients with the primary tumor in si... more We reviewed the outcomes of metastatic renal cell carcinoma patients with the primary tumor in situ who initially underwent interferon-a-based immunotherapy to evaluate the effect of this therapy on metastatic sites as well as primary kidney tumor and survival. Methods: Thirty-one patients, for whom upfront cytoreductive nephrectomy was considered to be inappropriate because of poor performance status and far-advanced disease, were the subject of the present study. Tumor response and reduction in the size of metastatic sites and primary kidney tumor were assessed. Overall survival distributions were estimated using the Kaplan-Meier method with the significance determined using the log-rank test. Results: Partial response was observed in 11 patients, yielding an overall response rate of 35%. Seventeen patients had regression or stabilization of metastatic sites, while progression of metastatic sites was observed in the remaining 14 patients. Regarding the maximum response of primary kidney tumor, a reduction in kidney primary tumor size was observed in 42% of the patients and the mean reduction rate in these patients was 18.2% (range: 3-36%). Furthermore, the reduction in the size of metastatic sites was significantly associated with that in the size of primary kidney tumor (R 2 ¼ 0.432, P , 0.0001). The median survival for the 31 patients was 17 months. The median survival was 42 months in patients with regression or stabilization of metastatic sites and 7 months in those without (P , 0.001). Conclusions: The present study suggests that metastatic sites as well as primary kidney tumor respond to interferon-a-based immunotherapy in metastatic renal cell carcinoma patients with primary tumor in situ.

International Journal of Oncology, 2010

Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts a... more Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts as a growth factor in several types of cancer cells. Our previous study revealed that an AM antagonist (AMA) suppressed the growth of pancreatic tumors in mice, although its mechanism was not elucidated. In this study, we constructed an AMA expression vector and used it to treat renal cell carcinoma (RCC) in mice. This AMA expression vector significantly reduced tumor growth in mice. In addition, microvessel density was decreased in AMA-treated tumors. To analyze the effect of AMA on tumor angiogenesis in this model, tumor endothelial cells (TECs) were isolated from RCC xenografts. TEC proliferation was stimulated by AM and it was inhibited by AMA significantly. AM induced migration of TECs and it was also blocked by AMA. However, normal ECs (NECs) were not affected by either AM or AMA. These results demonstrate that AMA has inhibitory effects on TECs specifically, not on NEC, thereby inhibiting tumor angiogenesis. Furthermore, we showed that vascular endothelial growth factor-induced mobilization of endothelial progenitor cell (EPC) into circulation was inhibited by AMA. These results suggest that AMA can be considered a good anti-angiogenic reagent that selectively targets TECs and EPC in renal cancer.

Cancer Science, 2017

Tumor blood vessels play an important role in tumor progression and metastasis. We previously rep... more Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH high TEC). ALDH high TEC have proangiogenic properties compared with ALDH low TEC. However, the association between ALDH high TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor-conditioned medium (tumor CM). The ALDH high population increased along with upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVEC. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDH high TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDH high TEC showed a higher grade of aneuploidy compared with that in ALDH low TEC. These results suggested that tumor-secreting factor increases ALDH high TEC populations that are resistant to 5-FU. Therefore, ALDH high TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.

PloS one, 2017

B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subs... more B cells constitute a complex system of antigen-presenting cells (APCs) and exist as distinct subsets that differ in their lineage affiliation, surface molecule expression, and biological function, thus potentially regulating the immune response. In this study, we investigated the immune-regulatory roles of murine B cell subsets as regulatory APCs targeting alloreactive T cells. Either splenic B cells, peritoneal cavity (PerC) B cells, or non-B cells from Balb/c mice were intravenously injected into B6 mice. Serum levels of anti-Balb/c antibodies in the recipients of PerC B cells were significantly lower than those in the recipients of splenic B cells and PerC non-B cells, as determined over a 4-week period after the injection. Mixed-lymphocyte reaction (MLR) assays using splenocytes from the B6 mice at 2 weeks after the injection revealed the significantly reduced anti-Balb/c T cell-responses in the recipients of PerC B cells, as compared to those in the recipients of splenic B cell...

Cancer science, Jan 7, 2017

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rat... more Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6 months in treatment-naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and updated safety in 44 Japanese patients and compared with 169 non-Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first-line metastatic RCC were explored using a Cox proportional hazard model in all patients. With median follow-up of 33 months, fewer than half (16 of 44) of Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9 months (95% CI, 28.9-42.7). Estimated 1-, 2-, and 3-year survival probability (95% CI) was 86.4% (76.2-96.5), 75.0% (62.2-87.8), and 68.2% (54.4-81.9), respectively, in Japanese pati...

Scientific reports, Jan 4, 2016

In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, a... more In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell line...

Japanese journal of clinical oncology, Jan 29, 2016

To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and... more To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, ...

The Journal of Urology, 2016

INTRODUCTION AND OBJECTIVES: The oncologic benefit of retroperitoneal lymph node dissection (LND)... more INTRODUCTION AND OBJECTIVES: The oncologic benefit of retroperitoneal lymph node dissection (LND) for patients undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC) has not been established. We investigated the association of LND with oncologic outcomes among patients undergoing CN. METHODS: We identified 305 patients treated with CN for M1 RCC between 1990 and 2010, of whom 188 (62%) underwent LND. A propensity score (PS) for receipt of LND was estimated using clinicopathologic features. The associations of LND with cancer-specific (CSM) and all-cause mortality (ACM) were evaluated using Cox regression models and several PS techniques including stratification by PS quintile, adjustment for PS quintile, and inverse probability weighting (IPW). Internally predicted probabilities for pN1 disease were estimated using logistic regression. RESULTS: Overall, 74 (24%) patients were pN1. After PS adjustment, there were no significant differences in clinicopathologic features according to receipt of LND. Median follow-up among survivors was 8.5 years, during which time 284 patients died, including 274 from RCC. In the overall cohort, LND was not significantly associated with CSM or ACM using any of the PS techniques (Table). We further examined whether LND was associated with survival outcomes among patients at increased risk of pN1 disease. Among patients with radiographically enlarged nodes (cN1), LND was not significantly associated with CSM or ACM. Moreover, across increasing threshold probabilities for pN1 disease of 20%, 40%, 60%, or 80%, LND was not associated with reduced CSM or ACM. CONCLUSIONS: Among patients undergoing CN for metastatic RCC, LND was not associated with improved oncologic outcomes in the overall cohort, for patients with radiographic cN1 disease, or across increasing probability thresholds for pN1 disease. These findings suggest that LND at the time of CN does not confer an oncologic benefit by cytoreduction of nodal metastases.

The Japanese Journal of Urology, 1995

BioMed Research International, 2015

Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carci... more Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC) and to identify prognostic factors. Methods. A single center retrospective study of 96 patients with mRCC from December 2004 to August 2013. Results. The median follow-up time was 45 months. Thirty-one (32.3%) of the patients received complete resection of metastatic sites, 11 (11.5%) of the patients underwent incomplete resection of metastatic sites, and 54 (56.3%) of the patients received no surgery. In the univariate Kaplan-Meier analysis, the median overall survival times of the three groups were 52 months, 16 months, and 22 months, respectively (p<0.001). The difference in the overall survival time was statistically significant between complete resection and no surgery groups (HR = 0.43, p=0.009), while there was no significant difference between the incomplete metastasectomy and no surgery groups (HR = 1.80, p=0.102). According to the multivariate Cox regression anal...

The New England journal of medicine, Jan 25, 2015

Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encou... more Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1...

Cancer science, Jan 25, 2015

A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with ... more 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-tyrosine kinase inhibitor (VEGF-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. VEGF-TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone me...

Cancer science, 2014

In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metast... more In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty-four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6-49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7-64.2); the median duration of response, 11.1 months (95% CI, 8.2-13.7); and the median progression-free survival was 11.0 months (95% CI, 9.2-12.0), assessed by the independent review committee. Common treatment-related all-grade adverse events were hypertension (88%), hand-foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and d...

BMC research notes, Jan 15, 2015

BackgroundRenal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clin... more BackgroundRenal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features.Case presentationA 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular ma...

PloS one, 2014

Tumor blood vessels play an important role in tumor progression and metastasis. It has been repor... more Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-...

Cancer science, 2014

Recent studies have reported that stromal cells contribute to tumor progression. We previously de... more Recent studies have reported that stromal cells contribute to tumor progression. We previously demonstrated that tumor endothelial cells (TEC) characteristics were different from those of normal endothelial cells (NEC). Furthermore, we performed gene profile analysis in TEC and NEC, revealing that suprabasin (SBSN) was upregulated in TEC compared with NEC. However, its role in TEC is still unknown. Here we showed that SBSN expression was higher in isolated human and mouse TEC than in NEC. SBSN knockdown inhibited the migration and tube formation ability of TEC. We also showed that the AKT pathway was a downstream factor of SBSN. These findings suggest that SBSN is involved in the angiogenic potential of TEC and may be a novel TEC marker.

Cancer science, Jan 28, 2015

We have previously reported that an adaptor protein CRK including CRK-I and CRK-II plays essentia... more 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 validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with a marked invasion, caused of distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry demonstrated a striking enhancement of CRK-I/-II, but not CRK-L, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which exhibited 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 HGF-dependent and -independent manner. In epithelial-mesenchymal transition (EMT)-related molecules, E-cadherin was up-regul...

Urologia Internationalis, 2011

Adult-onset Xp11.2 translocation renal cell carcinoma is a rare malignancy that has an aggressive... more Adult-onset Xp11.2 translocation renal cell carcinoma is a rare malignancy that has an aggressive clinical course and poor prognosis. The reasons for this include the fact that most patients have an advanced clinical stage at diagnosis and also that there is a lack of effective systemic therapy. We herein present the case of a 32-year-old woman suffering from node-positive Xp11.2 translocation renal cell carcinoma who underwent radical nephrectomy with an extensive retroperitoneal lymph node dissection, followed by two times of surgical resection for recurrent nodal disease. The patient has experienced no recurrent disease 4.5 years after the last operation and remains free of disease. Surgical approach to recurrent disease, if the recurrent site can be judged to be limited, might be one of the feasible treatment options in patients with Xp11.2 translocation renal cell carcinoma.

Journal of Clinical Oncology, 2010

Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 ... more Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). Methods Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. Results A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-fre...

Japanese Journal of Clinical Oncology, 2009

This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastat... more This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). Methods: Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECISTdefined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. Results: In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). Conclusions: In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.

Japanese Journal of Clinical Oncology, 2012

We reviewed the outcomes of metastatic renal cell carcinoma patients with the primary tumor in si... more We reviewed the outcomes of metastatic renal cell carcinoma patients with the primary tumor in situ who initially underwent interferon-a-based immunotherapy to evaluate the effect of this therapy on metastatic sites as well as primary kidney tumor and survival. Methods: Thirty-one patients, for whom upfront cytoreductive nephrectomy was considered to be inappropriate because of poor performance status and far-advanced disease, were the subject of the present study. Tumor response and reduction in the size of metastatic sites and primary kidney tumor were assessed. Overall survival distributions were estimated using the Kaplan-Meier method with the significance determined using the log-rank test. Results: Partial response was observed in 11 patients, yielding an overall response rate of 35%. Seventeen patients had regression or stabilization of metastatic sites, while progression of metastatic sites was observed in the remaining 14 patients. Regarding the maximum response of primary kidney tumor, a reduction in kidney primary tumor size was observed in 42% of the patients and the mean reduction rate in these patients was 18.2% (range: 3-36%). Furthermore, the reduction in the size of metastatic sites was significantly associated with that in the size of primary kidney tumor (R 2 ¼ 0.432, P , 0.0001). The median survival for the 31 patients was 17 months. The median survival was 42 months in patients with regression or stabilization of metastatic sites and 7 months in those without (P , 0.001). Conclusions: The present study suggests that metastatic sites as well as primary kidney tumor respond to interferon-a-based immunotherapy in metastatic renal cell carcinoma patients with primary tumor in situ.