Masakatsu Oishi

Apigenin Sensitizes Prostate Cancer Cells to Apo2L/TRAIL by Targeting Adenine Nucleotide Translocase-2

Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human Apo2L/TRAIL has been under clinical trials, whereas various kinds of malignant tumors have resistance to Apo2L/TRAIL. We and others have shown that several anticancer agents and flavonoids overcome resistance to Apo2L/TRAIL by upregulating death receptor 5 (DR5) in malignant tumor cells. However, the mechanisms by which these compounds induce DR5 expression remain unknown. Here we show that the dietary flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), resulting in enhancement of Apo2L/TRAIL-induced apoptosis by upregulation of DR5. Apigenin and genistein, which are major flavonoids, enhanced Apo2L/TRAIL-induced apoptosis in cancer cells. Apigenin induced DR5 expression, but genistein did not. Using our method identifying the direct targets of flavonoids, we compared the binding proteins of apigenin with those of genistein. We discovered that ANT2 was a target of apigenin, but not genistein. Similarly to apigenin, knockdown of ANT2 enhanced Apo2L/TRAIL-induced apoptosis by upregulating DR5 expression at the post-transcriptional level. Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest that apigenin upregulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by binding and inhibiting ANT2. We propose that ANT2 inhibitors may contribute to Apo2L/TRAIL therapy.

CDK1 and CDK2 activity is a strong predictor of renal cell carcinoma recurrence

BACKGROUND In renal cell carcinoma (RCC), the prediction of metastasis via tumor prognostic markers remains a major problem. The objective of our study was to evaluate the efficacy of cyclin-dependent kinase (CDK)1 and CDK2 activity as a prognostic marker in human RCC. METHODS Surgical specimens were obtained from 125 patients with RCC without metastasis. Protein expression and kinase activity of CDKs were analyzed using a newly developed assay system named C2P (Sysmex, Kobe, Japan). We then examined the specific activities (SAs) of CDK1 and CDK2 and calculated CDK2SA-CDK1SA ratio in RCC. Also, risk score (RS) was examined. RESULTS A total of 125 cases were tested, though 34 cases were excluded because of low sample quality (25 cases) and assay failure (9 cases). In total, 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow-up of 36 months (1-109M), tumor with low CDK2SA-CDK1SA ratio showed significantly better 5-year recurrence-free survival than those with high CDK2SA-CDK1SA ratio (88.7% vs. 54.7%, P = 0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, and patients with tumors classified as low RS showed better recurrence-free survival than patients with tumors with high RS (88.7% vs. 54.7%, P = 0.0141). CONCLUSION CDK1SA of tumors and the CDK2SA are both associated with recurrence and prognosis. IMPACT CDK-based risk demonstrated is strongly associated with clinical outcome. CDK-based risk should be an accurate system for predicting recurrence and survival for planning follow-up.

The flavonoid apigenin downregulates CDK1 by directly targeting ribosomal protein S9.

Flavonoids have been reported to inhibit tumor growth by causing cell cycle arrest. However, little is known about the direct targets of flavonoids in tumor growth inhibition. In the present study, we developed a novel method using magnetic FG beads to purify flavonoid-binding proteins, and identified ribosomal protein S9 (RPS9) as a binding partner of the flavonoid apigenin. Similar to treatment with apigenin, knockdown of RPS9 inhibited the growth of human colon cancer cells at the G2/M phase by downregulating cyclin-dependent kinase 1 (CDK1) expression at the promoter level. Furthermore, knockdown of RPS9 suppressed G2/M arrest caused by apigenin. These results suggest that apigenin induces G2/M arrest at least partially by directly binding and inhibiting RPS9 which enhances CDK1 expression. We therefore raise the possibility that identification of the direct targets of flavonoids may contribute to the discovery of novel molecular mechanisms governing tumor growth.

Transvesical laparoscopic surgery for double renal pelvis and ureter with or without ureterocele

To evaluate the performance of transvesical laparoscopic surgery for patients with complete double pelvis and ureter.

Importance of continuous sequential chemotherapy and multimodal treatment for advanced testicular cancer: a high-volume Japanese center experience.

AbstractPatients with “difficult-to-treat” advanced testicular cancer can require multiple therapies. We retrospectively assessed our patients with advanced germ cell tumors (GCTs) and characterized the clinical efficacy, outcomes, and factors affecting overall survival (OS).Two hundred fifty-three patients with advanced GCTs were treated at Kyoto Prefectural University of Medicine, Kyoto, Japan, from June 1998 to September 2013. Of 253 patients, 142 patients had salvage chemotherapy.As first-line therapy, bleomycin, etoposide, and cisplatin, and etoposide and cisplatin therapies were performed in 234 cases (92.5%). As second-line therapy, etoposide, ifosfamide, and cisplatin/vinblastine, ifosfamide, and cisplatin, and paclitaxel, ifosfamide, and cisplatin/paclitaxel, ifosfamide, and nedaplatin therapies were carried out in 44 and 59 cases, respectively. Furthermore, 111, 72, 44, and 28 cases had third, fourth, fifth, and sixth-or-later-line chemotherapy, respectively. Five-year OS rate stratified by chemotherapy line was 95.5% in the first line, 89.4% in the second line, 82.1% in the third line, 45.1% in the fourth line, and 58.9% in the fifth or after line. A statistical significant difference was found when comparing fourth-or-after-line versus first to third-line therapy. Additional procedures were performed, including retroperitoneal lymph node dissection (RPLND) (n = 168), extra-RPLN resection (n = 114), and external beam radiotherapy/stereotactic radiotherapy (n = 78).Multivariate analysis showed that factors predicting better outcomes were in serum tumor marker (STM) normalization, RPLND, and extra-RPLN resection.Good outcomes were obtained in patients who completed chemotherapy up to third line. After fourth-line chemotherapy, approximately 50% of “difficult-to-treat” patients could be cured with normalization of STM levels and residual mass resection. Continuous or sequential chemotherapy with multimodality therapy is important for patients with “difficult-to-treat” advanced GCTs. Effective chemotherapy after third line should be developed.

Therapy‐related acute myeloid leukemia and myelodysplastic syndrome among refractory germ cell tumor patients

To analyze cases of therapy‐related acute myeloid leukemia and myelodysplastic syndrome diagnosed after chemotherapy for refractory testicular and extragonadal germ cell tumor in our experience.

Salvage combined chemotherapy with paclitaxel, ifosfamide and nedaplatin for patients with advanced germ cell tumors.

To investigate the efficacy of combined regimen with paclitaxel, ifosfamide and nedaplatin as salvage chemotherapy in patients with cisplatin‐refractory or multiple relapsed germ cell tumors.

Clinical outcomes and histological findings of patients with advanced metastatic germ cell tumors undergoing post-chemotherapy resection of retroperitoneal lymph nodes and residual extraretroperitoneal masses.

To assess clinical outcomes of patients with advanced germ cell tumor undergoing post‐chemotherapy retroperitoneal lymph node dissection with or without extraretroperitoneal mass resection.

Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). METHODS We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. RESULTS A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). CONCLUSIONS Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.

Which Patients with Negative Magnetic Resonance Imaging Can Safely Avoid Biopsy for Prostate Cancer

Purpose: We sought to determine whether there is a subset of men who can avoid prostate biopsy based on multiparametric magnetic resonance imaging and clinical characteristics. Materials and Methods: Of 1,149 consecutive men who underwent prostate biopsy from October 2011 to March 2017, 135 had prebiopsy negative multiparametric magnetic resonance imaging with PI-RADS™ (Prostate Imaging Reporting and Data System) score less than 3. The detection rate of clinically significant prostate cancer was evaluated according to prostate specific antigen density and prior biopsy history. Clinically significant prostate cancer was defined as Grade Group 2 or greater. Multivariable logistic regression analysis was performed to identify predictors of nonclinically significant prostate cancer on biopsy. Results: The prostate cancer and clinically significant prostate cancer detection rates were 38% and 18%, respectively. Men with biopsy detected, clinically significant prostate cancer had a smaller prostate (p = 0.004), higher prostate specific antigen density (p = 0.02) and no history of prior negative biopsy (p = 0.01) compared to the nonclinically significant prostate cancer cohort. Prostate specific antigen density less than 0.15 ng/ml/cc (p <0.001) and prior negative biopsy (p = 0.005) were independent predictors of absent clinically significant prostate cancer on biopsy. The negative predictive value of multiparametric magnetic resonance imaging for biopsy detection of clinically significant prostate cancer improved with decreasing prostate specific antigen density, primarily in men with prior negative biopsy (p = 0.001) but not in biopsy naïve men. Of the men 32% had the combination of negative multiparametric magnetic resonance imaging, prostate specific antigen density less than 0.15 ng/ml/cc and negative prior biopsy, and none had clinically significant prostate cancer on repeat biopsy. The incidence of biopsy identified, clinically significant prostate cancer was 18%, 10% and 0% in men with negative multiparametric magnetic resonance imaging only, men with negative multiparametric magnetic resonance imaging and prostate specific antigen density less than 0.15 ng/ml/cc, and men with negative multiparametric magnetic resonance imaging, prostate specific antigen density less than 0.15 ng/ml/cc and negative prior biopsy, respectively. Conclusions: We propose that a subset of men with negative multiparametric magnetic resonance imaging, prostate specific antigen density less than 0.15 ng/ml/cc and prior negative biopsy may safely avoid rebiopsy. Conversely prostate biopsy should be considered in biopsy naïve men regardless of negative multiparametric magnetic resonance imaging, particularly those with prostate specific antigen density greater than 0.15 ng/ml/cc.